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Lou Y, Jiang Q, Huang S, Xie Y, Wang H, Wang L, Wang S, Xu M, Lu Z, Wang F, Cao S. Association of dietary diversity and weight change with cognitive impairment among Chinese elderly: A prospective national cohort study. J Affect Disord 2025; 368:789-797. [PMID: 39271068 DOI: 10.1016/j.jad.2024.09.057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 07/27/2024] [Accepted: 09/10/2024] [Indexed: 09/15/2024]
Abstract
BACKGROUND Dietary diversity is reported to be beneficial for cognitive function, while the effect may be offset by weight change status. We aimed to examine the association of dietary diversity and weight change with cognitive impairment among older adults. METHODS We used three waves from 2008 to 2014 of the Chinese Longitudinal Survey of Health and Longevity, which included 16,954 participants for the subsequent screening and analysis. Dietary diversity information was collected from the food frequency questionnaire. Cognitive function was assessed using the Mini Mental State Examination. The relation of dietary diversity and weight change with cognitive impairment was investigated using Cox proportional hazards models and cubic spline regression. RESULTS Compared with those reported poor dietary diversity at baseline, participants with good dietary diversity had a 16 % (hazard ratio [HR] = 0.84, 95 % confidence interval [CI]: 0.71-0.99) lower risk of cognitive impairment. The HR and 95 % CI of participants with consistently good dietary diversity from 2008 to 2011 was 0.71 (0.57-0.89) for cognitive impairment compared to those with consistently poor dietary diversity. Compared with the weight stable group, the HRs and 95 % CI for cognitive impairment were 1.34 (1.10-1.64) in weight loss group, and 1.08 (0.88-1.33) in weight gain group. Restricted cubic splines showed the risk of cognitive impairment decreased with higher dietary diversity score or less weight change, though no significant interaction between dietary diversity and weight change was found. LIMITATION Given the observational nature of this study, there might be a reverse causation for the observed association. CONCLUSION Establishing and maintaining good dietary diversity were associated with a lower risk of cognitive impairment regardless of weight change status, whereas weight loss was associated with increased cognitive impairment risk independently among older Chinese adults.
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Affiliation(s)
- Yiling Lou
- School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Qingqing Jiang
- School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Shen Huang
- School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Yulin Xie
- School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Hengchang Wang
- School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Linlin Wang
- School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Shiqi Wang
- School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Minzhi Xu
- School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Zuxun Lu
- School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Furong Wang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Shiyi Cao
- School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
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Oliveira-Paula GH, Martins AC, Ferrer B, Tinkov AA, Skalny AV, Aschner M. The impact of manganese on vascular endothelium. Toxicol Res 2024; 40:501-517. [PMID: 39345740 PMCID: PMC11436708 DOI: 10.1007/s43188-024-00260-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Revised: 07/10/2024] [Accepted: 07/26/2024] [Indexed: 10/01/2024] Open
Abstract
Manganese (Mn) is an essential trace element involved in various physiological processes, but excessive exposure may lead to toxicity. The vascular endothelium, a monolayer of endothelial cells within blood vessels, is a primary target of Mn toxicity. This review provides a comprehensive overview of the impact of Mn on vascular endothelium, focusing on both peripheral and brain endothelial cells. In vitro studies have demonstrated that high concentrations of Mn can induce endothelial cell cytotoxicity, increase permeability, and disrupt cell-cell junctions through mechanisms involving oxidative stress, mitochondrial damage, and activation of signaling pathways, such as Smad2/3-Snail. Conversely, low concentrations of Mn may protect endothelial cells from the deleterious effects of high glucose and advanced glycation end-products. In the central nervous system, Mn can cross the blood-brain barrier (BBB) and accumulate in the brain parenchyma, leading to neurotoxicity. Several transport mechanisms, including ZIP8, ZIP14, and SPCA1, have been identified for Mn uptake by brain endothelial cells. Mn exposure can impair BBB integrity by disrupting tight junctions and increasing permeability. In vivo studies have corroborated these findings, highlighting the importance of endothelial barriers in mediating Mn toxicity in the brain and kidneys. Maintaining optimal Mn homeostasis is crucial for preserving endothelial function, and further research is needed to develop targeted therapeutic strategies to prevent or mitigate the adverse effects of Mn overexposure. Graphical Abstract
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Affiliation(s)
| | - Airton C. Martins
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461 USA
| | - Beatriz Ferrer
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461 USA
| | - Alexey A. Tinkov
- Laboratory of Ecobiomonitoring and Quality Control, Yaroslavl State University, Yaroslavl, 150003 Russia
- IM Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119435 Russia
| | - Anatoly V. Skalny
- Laboratory of Ecobiomonitoring and Quality Control, Yaroslavl State University, Yaroslavl, 150003 Russia
- IM Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119435 Russia
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461 USA
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Abdulhameed N, Babin A, Hansen K, Weaver R, Banks WA, Talbot K, Rhea EM. Comparing regional brain uptake of incretin receptor agonists after intranasal delivery in CD-1 mice and the APP/PS1 mouse model of Alzheimer's disease. Alzheimers Res Ther 2024; 16:173. [PMID: 39085976 PMCID: PMC11293113 DOI: 10.1186/s13195-024-01537-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 07/17/2024] [Indexed: 08/02/2024]
Abstract
Targeting brain insulin resistance (BIR) has become an attractive alternative to traditional therapeutic treatments for Alzheimer's disease (AD). Incretin receptor agonists (IRAs), targeting either or both of the glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, have proven to reverse BIR and improve cognition in mouse models of AD. We previously showed that many, but not all, IRAs can cross the blood-brain barrier (BBB) after intravenous (IV) delivery. Here we determined if widespread brain uptake of IRAs could be achieved by circumventing the BBB using intranasal (IN) delivery, which has the added advantage of minimizing adverse gastrointestinal effects of systemically delivered IRAs. Of the 5 radiolabeled IRAs tested (exenatide, dulaglutide, semaglutide, DA4-JC, and DA5-CH) in CD-1 mice, exenatide, dulaglutide, and DA4-JC were successfully distributed throughout the brain following IN delivery. We observed significant sex differences in uptake for DA4-JC. Dulaglutide and DA4-JC exhibited high uptake by the hippocampus and multiple neocortical areas. We further tested and found the presence of AD-associated Aβ pathology minimally affected uptake of dulaglutide and DA4-JC. Of the 5 tested IRAs, dulaglutide and DA4-JC are best capable of accessing brain regions most vulnerable in AD (neocortex and hippocampus) after IN administration. Future studies will need to be performed to determine if IN IRA delivery can reduce BIR in AD or animal models of that disorder.
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Affiliation(s)
- Noor Abdulhameed
- Veterans Affairs Puget Sound Health Care System, Geriatrics Research Education and Clinical Center, 1660 S. Columbian Way, Seattle, WA, 98108, USA
| | - Alice Babin
- Veterans Affairs Puget Sound Health Care System, Geriatrics Research Education and Clinical Center, 1660 S. Columbian Way, Seattle, WA, 98108, USA
| | - Kim Hansen
- Veterans Affairs Puget Sound Health Care System, Geriatrics Research Education and Clinical Center, 1660 S. Columbian Way, Seattle, WA, 98108, USA
| | - Riley Weaver
- Veterans Affairs Puget Sound Health Care System, Geriatrics Research Education and Clinical Center, 1660 S. Columbian Way, Seattle, WA, 98108, USA
| | - William A Banks
- Veterans Affairs Puget Sound Health Care System, Geriatrics Research Education and Clinical Center, 1660 S. Columbian Way, Seattle, WA, 98108, USA
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, 98498, USA
| | - Konrad Talbot
- Departments of Neurosurgery, Pathology and Human Anatomy, and Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, 92354, USA.
| | - Elizabeth M Rhea
- Veterans Affairs Puget Sound Health Care System, Geriatrics Research Education and Clinical Center, 1660 S. Columbian Way, Seattle, WA, 98108, USA.
- Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, 98498, USA.
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Zhou AL, Swaminathan SK, Salian VS, Wang L, Curran GL, Min HK, Lowe VJ, Kandimalla KK. Insulin Signaling Differentially Regulates the Trafficking of Insulin and Amyloid Beta Peptides at the Blood-Brain Barrier. Mol Pharm 2024; 21:2176-2186. [PMID: 38625027 PMCID: PMC11929044 DOI: 10.1021/acs.molpharmaceut.3c00784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/17/2024]
Abstract
The blood-brain barrier (BBB) is instrumental in clearing toxic metabolites from the brain, such as amyloid-β (Aβ) peptides, and in delivering essential nutrients to the brain, like insulin. In Alzheimer's disease (AD) brain, increased Aβ levels are paralleled by decreased insulin levels, which are accompanied by insulin signaling deficits at the BBB. Thus, we investigated the impact of insulin-like growth factor and insulin receptor (IGF1R and IR) signaling on Aβ and insulin trafficking at the BBB. Following intravenous infusion of an IGF1R/IR kinase inhibitor (AG1024) in wild-type mice, the BBB trafficking of 125I radiolabeled Aβ peptides and insulin was assessed by dynamic SPECT/CT imaging. The brain efflux of [125I]iodo-Aβ42 decreased upon AG1024 treatment. Additionally, the brain influx of [125I]iodoinsulin, [125I]iodo-Aβ42, [125I]iodo-Aβ40, and [125I]iodo-BSA (BBB integrity marker) was decreased, increased, unchanged, and unchanged, respectively, upon AG1024 treatment. Subsequent mechanistic studies were performed using an in vitro BBB cell model. The cell uptake of [125I]iodoinsulin, [125I]iodo-Aβ42, and [125I]iodo-Aβ40 was decreased, increased, and unchanged, respectively, upon AG1024 treatment. Further, AG1024 reduced the phosphorylation of insulin signaling kinases (Akt and Erk) and the membrane expression of Aβ and insulin trafficking receptors (LRP-1 and IR-β). These findings reveal that insulin signaling differentially regulates the BBB trafficking of Aβ peptides and insulin. Moreover, deficits in IGF1R and IR signaling, as observed in the brains of type II diabetes and AD patients, are expected to increase Aβ accumulation while decreasing insulin delivery to the brain, which has been linked to the progression of cognitive decline in AD.
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Affiliation(s)
- Andrew L Zhou
- Department of Pharmaceutics and Brain Barriers Research Center, University of Minnesota College of Pharmacy, Minneapolis, Minnesota 55455, United States
| | - Suresh K Swaminathan
- Department of Pharmaceutics and Brain Barriers Research Center, University of Minnesota College of Pharmacy, Minneapolis, Minnesota 55455, United States
| | - Vrishali S Salian
- Department of Pharmaceutics and Brain Barriers Research Center, University of Minnesota College of Pharmacy, Minneapolis, Minnesota 55455, United States
| | - Lushan Wang
- Department of Pharmaceutics and Brain Barriers Research Center, University of Minnesota College of Pharmacy, Minneapolis, Minnesota 55455, United States
| | - Geoffry L Curran
- Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, United States
- Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, United States
| | - Hoon-Ki Min
- Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, United States
| | - Val J Lowe
- Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, United States
| | - Karunya K Kandimalla
- Department of Pharmaceutics and Brain Barriers Research Center, University of Minnesota College of Pharmacy, Minneapolis, Minnesota 55455, United States
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Hanafy AS, Lamprecht A, Dietrich D. Local perfusion of capillaries reveals disrupted beta-amyloid homeostasis at the blood-brain barrier in Tg2576 murine Alzheimer's model. Fluids Barriers CNS 2023; 20:85. [PMID: 37993886 PMCID: PMC10666337 DOI: 10.1186/s12987-023-00492-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 11/19/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND Parenchymal accumulation of beta-amyloid (Aβ) characterizes Alzheimer's disease (AD). Aβ homeostasis is maintained by two ATP-binding cassette (ABC) transporters (ABCC1 and ABCB1) mediating efflux, and the receptor for advanced glycation end products (RAGE) mediating influx across the blood-brain barrier (BBB). Altered transporter levels and disruption of tight junctions (TJ) were linked to AD. However, Aβ transport and the activity of ABCC1, ABCB1 and RAGE as well as the functionality of TJ in AD are unclear. METHODS ISMICAP, a BBB model involving microperfusion of capillaries, was used to assess BBB properties in acute cortical brain slices from Tg2576 mice compared to wild-type (WT) controls using two-photon microscopy. TJ integrity was tested by vascularly perfusing biocytin-tetramethylrhodamine (TMR) and quantifying its extravascular diffusion as well as the diffusion of FM1-43 from luminal to abluminal membranes of endothelial cells (ECs). To assess ABCC1 and ABCB1 activity, calcein-AM was perfused, which is converted to fluorescent calcein in ECs and gets actively extruded by both transporters. To probe which transporter is involved, probenecid or Elacridar were applied, individually or combined, to block ABCC1 and ABCB1, respectively. To assess RAGE activity, the binding of 5-FAM-tagged Aβ by ECs was quantified with or without applying FPS-ZM1, a RAGE antagonist. RESULTS In Tg2576 mouse brain, extravascular TMR was 1.8-fold that in WT mice, indicating increased paracellular leakage. FM1-43 staining of abluminal membranes in Tg2576 capillaries was 1.7-fold that in WT mice, indicating reduced TJ integrity in AD. While calcein was undetectable in WT mice, its accumulation was significant in Tg2576 mice, suggesting lower calcein extrusion in AD. Incubation with probenecid or Elacridar in WT mice resulted in a marked calcein accumulation, yet probenecid alone had no effect in Tg2576 mice, implying the absence of probenecid-sensitive ABC transporters. In WT mice, Aβ accumulated along the luminal membranes, which was undetectable after applying FPS-ZM1. In contrast, marginal Aβ fluorescence was observed in Tg2576 vessels, and FPS-ZM1 was without effect, suggesting reduced RAGE binding activity. CONCLUSIONS Disrupted TJ integrity, reduced ABCC1 functionality and decreased RAGE binding were identified as BBB alterations in Tg2576 mice, with the latter finding challenging the current concepts. Our results suggest to manage AD by including modulation of TJ proteins and Aβ-RAGE binding.
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Affiliation(s)
- Amira Sayed Hanafy
- Department of Neurosurgery, University Hospital Bonn, Bonn, Germany.
- Department of Pharmaceutics, Institute of Pharmacy, University of Bonn, Bonn, Germany.
| | - Alf Lamprecht
- Department of Pharmaceutics, Institute of Pharmacy, University of Bonn, Bonn, Germany
| | - Dirk Dietrich
- Department of Neurosurgery, University Hospital Bonn, Bonn, Germany
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Lee S, Byun MS, Yi D, Kim MJ, Jung JH, Kong N, Jung G, Ahn H, Lee JY, Kang KM, Sohn CH, Lee YS, Kim YK, Lee DY. Body mass index and two-year change of in vivo Alzheimer's disease pathologies in cognitively normal older adults. Alzheimers Res Ther 2023; 15:108. [PMID: 37312229 DOI: 10.1186/s13195-023-01259-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 06/01/2023] [Indexed: 06/15/2023]
Abstract
BACKGROUND Low body mass index (BMI) or underweight status in late life is associated with an increased risk of dementia or Alzheimer's disease (AD). However, the relationship between late-life BMI and prospective longitudinal changes of in-vivo AD pathology has not been investigated. METHODS This prospective longitudinal study was conducted as part of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE). A total of 194 cognitive normal older adults were included in the analysis. BMI at baseline was measured, and two-year changes in brain Aβ and tau deposition on PET imaging were used as the main outcomes. Linear mixed-effects (LME) models were used to examine the relationships between late-life BMI and longitudinal change in AD neuropathological biomarkers. RESULTS A lower BMI at baseline was significantly associated with a greater increase in tau deposition in AD-signature region over 2 years (β, -0.018; 95% CI, -0.028 to -0.004; p = .008), In contrast, BMI was not related to two-year changes in global Aβ deposition (β, 0.0002; 95% CI, -0.003 to 0.002, p = .671). An additional exploratory analysis for each sex showed lower baseline BMI was associated with greater increases in tau deposition in males (β, -0.027; 95% CI, -0.046 to -0.009; p = 0.007), but not in females. DISCUSSION The findings suggest that lower BMI in late-life may predict or contribute to the progression of tau pathology over the subsequent years in cognitively unimpaired older adults.
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Affiliation(s)
- Seunghoon Lee
- Department of Psychiatry, Myongji Hospital, Hanyang University College of Medicine, Goyang, 10475, Republic of Korea
| | - Min Soo Byun
- Department of Neuropsychiatry, Seoul National University Hospital, Seoul, 03080, Republic of Korea
- Department of Psychiatry, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Dahyun Yi
- Institute of Human Behavioral Medicine, Medical Research Center, Seoul National University, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Republic of Korea
| | - Min Jung Kim
- Department of Neuropsychiatry, Nowon Eulji University Hospital, Seoul, 01830, Republic of Korea
| | - Joon Hyung Jung
- Department of Neuropsychiatry, Seoul National University Hospital, Seoul, 03080, Republic of Korea
| | - Nayeong Kong
- Department of Neuropsychiatry, Seoul National University Hospital, Seoul, 03080, Republic of Korea
| | - Gijung Jung
- Institute of Human Behavioral Medicine, Medical Research Center, Seoul National University, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Republic of Korea
| | - Hyejin Ahn
- Institute of Human Behavioral Medicine, Medical Research Center, Seoul National University, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Republic of Korea
| | - Jun-Young Lee
- Department of Neuropsychiatry, SMG-SNU Boramae Medical Center, Seoul, 07061, Republic of Korea
| | - Koung Mi Kang
- Department of Radiology, Seoul National University Hospital, Seoul, 03080, Republic of Korea
| | - Chul-Ho Sohn
- Department of Radiology, Seoul National University Hospital, Seoul, 03080, Republic of Korea
| | - Yun-Sang Lee
- Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Yu Kyeong Kim
- Department of Nuclear Medicine, SMG-SNU Boramae Medical Center, Seoul, 07061, Republic of Korea
| | - Dong Young Lee
- Department of Neuropsychiatry, Seoul National University Hospital, Seoul, 03080, Republic of Korea.
- Department of Psychiatry, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
- Institute of Human Behavioral Medicine, Medical Research Center, Seoul National University, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Republic of Korea.
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Napper S, Schatzl HM. Oral vaccination as a potential strategy to manage chronic wasting disease in wild cervid populations. Front Immunol 2023; 14:1156451. [PMID: 37122761 PMCID: PMC10140515 DOI: 10.3389/fimmu.2023.1156451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 03/31/2023] [Indexed: 05/02/2023] Open
Abstract
Prion diseases are a novel class of infectious disease based in the misfolding of the cellular prion protein (PrPC) into a pathological, self-propagating isoform (PrPSc). These fatal, untreatable neurodegenerative disorders affect a variety of species causing scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in cervids, and Creutzfeldt-Jacob disease (CJD) in humans. Of the animal prion diseases, CWD is currently regarded as the most significant threat due its ongoing geographical spread, environmental persistence, uptake into plants, unpredictable evolution, and emerging evidence of zoonotic potential. The extensive efforts to manage CWD have been largely ineffective, highlighting the need for new disease management tools, including vaccines. Development of an effective CWD vaccine is challenged by the unique biology of these diseases, including the necessity, and associated dangers, of overcoming immune tolerance, as well the logistical challenges of vaccinating wild animals. Despite these obstacles, there has been encouraging progress towards the identification of safe, protective antigens as well as effective strategies of formulation and delivery that would enable oral delivery to wild cervids. In this review we highlight recent strategies for antigen selection and optimization, as well as considerations of various platforms for oral delivery, that will enable researchers to accelerate the rate at which candidate CWD vaccines are developed and evaluated.
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Affiliation(s)
- Scott Napper
- Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Hermann M. Schatzl
- Calgary Prion Research Unit, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
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Banks WA, Noonan C, Rhea EM. Evidence for an alternative insulin transporter at the blood-brain barrier. AGING PATHOBIOLOGY AND THERAPEUTICS 2022; 4:100-108. [PMID: 36644126 PMCID: PMC9837797 DOI: 10.31491/apt.2022.12.100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Accumulating evidence suggests there is an alternative insulin transporter besides the insulin receptor at the blood-brain barrier (BBB), responsible for shuttling insulin from the circulation into the brain. In this review, we summarize key features of the BBB and what makes it unique compared to other capillary beds; summarize what we know about insulin BBB transport; provide an extensive list of diseases, physiological states, and serum factors tested in modifying insulin BBB transport; and lastly, highlight potential alternative transport systems that may be involved in or have already been tested in mediating insulin BBB transport. Identifying the transport system for insulin at the BBB would aide in controlling central nervous system (CNS) insulin levels in multiple diseases and conditions including Alzheimer's disease (AD) and obesity, where availability of insulin to the CNS is limited.
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Affiliation(s)
- William A. Banks
- Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA 98195, USA
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
| | - Cassidy Noonan
- Research and Development, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
- University of Washington, Seattle, WA 98195, USA
| | - Elizabeth M. Rhea
- Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA 98195, USA
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA
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Nehra G, Bauer B, Hartz AMS. Blood-brain barrier leakage in Alzheimer's disease: From discovery to clinical relevance. Pharmacol Ther 2022; 234:108119. [PMID: 35108575 PMCID: PMC9107516 DOI: 10.1016/j.pharmthera.2022.108119] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/14/2022] [Accepted: 01/18/2022] [Indexed: 12/16/2022]
Abstract
Alzheimer's disease (AD) is the most common form of dementia. AD brain pathology starts decades before the onset of clinical symptoms. One early pathological hallmark is blood-brain barrier dysfunction characterized by barrier leakage and associated with cognitive decline. In this review, we summarize the existing literature on the extent and clinical relevance of barrier leakage in AD. First, we focus on AD animal models and their susceptibility to barrier leakage based on age and genetic background. Second, we re-examine barrier dysfunction in clinical and postmortem studies, summarize changes that lead to barrier leakage in patients and highlight the clinical relevance of barrier leakage in AD. Third, we summarize signaling mechanisms that link barrier leakage to neurodegeneration and cognitive decline in AD. Finally, we discuss clinical relevance and potential therapeutic strategies and provide future perspectives on investigating barrier leakage in AD. Identifying mechanistic steps underlying barrier leakage has the potential to unravel new targets that can be used to develop novel therapeutic strategies to repair barrier leakage and slow cognitive decline in AD and AD-related dementias.
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Affiliation(s)
- Geetika Nehra
- Sanders-Brown Center on Aging, College of Medicine, University of Kentucky, Lexington, KY, USA
| | - Bjoern Bauer
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA
| | - Anika M S Hartz
- Sanders-Brown Center on Aging, College of Medicine, University of Kentucky, Lexington, KY, USA; Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY, USA.
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Frank CJ, McNay EC. Breakdown of the blood-brain barrier: A mediator of increased Alzheimer's risk in patients with metabolic disorders? J Neuroendocrinol 2022; 34:e13074. [PMID: 34904299 PMCID: PMC8791015 DOI: 10.1111/jne.13074] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 11/12/2021] [Accepted: 11/26/2021] [Indexed: 01/03/2023]
Abstract
Metabolic disorders (MDs), including type 1 and 2 diabetes and chronic obesity, are among the faster growing diseases globally and are a primary risk factor for Alzheimer's disease (AD). The term "type-3 diabetes" has been proposed for AD due to the interrelated cellular, metabolic, and immune features shared by diabetes, insulin resistance (IR), and the cognitive impairment and neurodegeneration found in AD. Patients with MDs and/or AD commonly exhibit altered glucose homeostasis and IR; systemic chronic inflammation encompassing all of the periphery, blood-brain barrier (BBB), and central nervous system; pathological vascular remodeling; and increased BBB permeability that allows transfusion of neurotoxic molecules from the blood to the brain. This review summarizes the components of the BBB, mechanisms through which MDs alter BBB permeability via immune and metabolic pathways, the contribution of BBB dysfunction to the manifestation and progression of AD, and current avenues of therapeutic research that address BBB permeability. In addition, issues with the translational applicability of current animal models of AD regarding BBB dysfunction and proposals for future directions of research that address the relationship between MDs, BBB dysfunction, and AD are discussed.
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Affiliation(s)
- Corey J Frank
- Behavioral Neuroscience, University at Albany, SUNY, Albany, NY, USA
| | - Ewan C McNay
- Behavioral Neuroscience, University at Albany, SUNY, Albany, NY, USA
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Szu JI, Obenaus A. Cerebrovascular phenotypes in mouse models of Alzheimer's disease. J Cereb Blood Flow Metab 2021; 41:1821-1841. [PMID: 33557692 PMCID: PMC8327123 DOI: 10.1177/0271678x21992462] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 12/16/2020] [Accepted: 01/06/2021] [Indexed: 12/12/2022]
Abstract
Alzheimer's disease (AD) is a devastating neurological degenerative disorder and is the most common cause of dementia in the elderly. Clinically, AD manifests with memory and cognitive decline associated with deposition of hallmark amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs). Although the mechanisms underlying AD remains unclear, two hypotheses have been proposed. The established amyloid hypothesis states that Aβ accumulation is the basis of AD and leads to formation of NFTs. In contrast, the two-hit vascular hypothesis suggests that early vascular damage leads to increased accumulation of Aβ deposits in the brain. Multiple studies have reported significant morphological changes of the cerebrovasculature which can result in severe functional deficits. In this review, we delve into known structural and functional vascular alterations in various mouse models of AD and the cellular and molecular constituents that influence these changes to further disease progression. Many studies shed light on the direct impact of Aβ on the cerebrovasculature and how it is disrupted during the progression of AD. However, more research directed towards an improved understanding of how the cerebrovasculature is modified over the time course of AD is needed prior to developing future interventional strategies.
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Affiliation(s)
- Jenny I Szu
- Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA, USA
| | - André Obenaus
- Department of Pediatrics, University of California Irvine, Irvine, CA, USA
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12
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Taccola C, Barneoud P, Cartot-Cotton S, Valente D, Schussler N, Saubaméa B, Chasseigneaux S, Cochois V, Mignon V, Curis E, Lochus M, Nicolic S, Dodacki A, Cisternino S, Declèves X, Bourasset F. Modifications of physical and functional integrity of the blood-brain barrier in an inducible mouse model of neurodegeneration. Neuropharmacology 2021; 191:108588. [PMID: 33940010 DOI: 10.1016/j.neuropharm.2021.108588] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 04/10/2021] [Accepted: 04/20/2021] [Indexed: 12/28/2022]
Abstract
The inducible p25 overexpression mouse model recapitulate many hallmark features of Alzheimer's disase including progressive neuronal loss, elevated Aβ, tau pathology, cognitive dysfunction, and impaired synaptic plasticity. We chose p25 mice to evaluate the physical and functional integrity of the blood-brain barrier (BBB) in a context of Tau pathology (pTau) and severe neurodegeneration, at an early (3 weeks ON) and a late (6 weeks ON) stage of the pathology. Using in situ brain perfusion and confocal imaging, we found that the brain vascular surface area and the physical integrity of the BBB were unaltered in p25 mice. However, there was a significant 14% decrease in cerebrovascular volume in 6 weeks ON mice, possibly explained by a significant 27% increase of collagen IV in the basement membrane of brain capillaries. The function of the BBB transporters GLUT1 and LAT1 was evaluated by measuring brain uptake of d-glucose and phenylalanine, respectively. In 6 weeks ON p25 mice, d-glucose brain uptake was significantly reduced by about 17% compared with WT, without any change in the levels of GLUT1 protein or mRNA in brain capillaries. The brain uptake of phenylalanine was not significantly reduced in p25 mice compared with WT. Lack of BBB integrity, impaired BBB d-glucose transport have been observed in several mouse models of AD. In contrast, reduced cerebrovascular volume and an increased basement membrane thickness may be more specifically associated with pTau in mouse models of neurodegeneration.
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Affiliation(s)
- Camille Taccola
- Pharmacokinetics, Dynamics and Metabolism, Translational Medicine & Early Development, Sanofi, 3 Digue d'Alfortville, 94140, Alfortville, France; INSERM UMR-S 1144, UFR de Pharmacie, Faculté de Santé, Université de Paris, 4 avenue de l'Observatoire, 75006, Paris, France
| | - Pascal Barneoud
- Rare and Neurologic Diseases Research Therapeutic Area, Sanofi, 1 Avenue Pierre Brossolette, 91380, Chilly-Mazarin, France
| | - Sylvaine Cartot-Cotton
- Pharmacokinetics, Dynamics and Metabolism, Translational Medicine & Early Development, Sanofi, 3 Digue d'Alfortville, 94140, Alfortville, France
| | - Delphine Valente
- Drug Metabolism & Pharmacokinetics, Research platform, Sanofi, 3 Digue d'Alfortville, 94140, Alfortville, France
| | - Nathalie Schussler
- Rare and Neurologic Diseases Research Therapeutic Area, Sanofi, 1 Avenue Pierre Brossolette, 91380, Chilly-Mazarin, France
| | - Bruno Saubaméa
- INSERM UMR-S 1144, UFR de Pharmacie, Faculté de Santé, Université de Paris, 4 avenue de l'Observatoire, 75006, Paris, France
| | - Stéphanie Chasseigneaux
- INSERM UMR-S 1144, UFR de Pharmacie, Faculté de Santé, Université de Paris, 4 avenue de l'Observatoire, 75006, Paris, France
| | - Véronique Cochois
- INSERM UMR-S 1144, UFR de Pharmacie, Faculté de Santé, Université de Paris, 4 avenue de l'Observatoire, 75006, Paris, France
| | - Virginie Mignon
- INSERM UMR-S 1144, UFR de Pharmacie, Faculté de Santé, Université de Paris, 4 avenue de l'Observatoire, 75006, Paris, France
| | - Emmanuel Curis
- Laboratoire de biomathématiques, plateau iB(2), EA 7537 « BioSTM », UFR de Pharmacie, Faculté de Santé, Université de Paris, 4 avenue de l'Observatoire, 75006, Paris, France; Service de bioinformatique et statistique médicale, hôpital Saint-Louis, APHP, 1, avenue Claude Vellefaux, 75010, Paris, France
| | - Murielle Lochus
- INSERM UMR-S 1144, UFR de Pharmacie, Faculté de Santé, Université de Paris, 4 avenue de l'Observatoire, 75006, Paris, France
| | - Sophie Nicolic
- INSERM UMR-S 1144, UFR de Pharmacie, Faculté de Santé, Université de Paris, 4 avenue de l'Observatoire, 75006, Paris, France
| | - Agnès Dodacki
- INSERM UMR-S 1144, UFR de Pharmacie, Faculté de Santé, Université de Paris, 4 avenue de l'Observatoire, 75006, Paris, France
| | - Salvatore Cisternino
- INSERM UMR-S 1144, UFR de Pharmacie, Faculté de Santé, Université de Paris, 4 avenue de l'Observatoire, 75006, Paris, France
| | - Xavier Declèves
- INSERM UMR-S 1144, UFR de Pharmacie, Faculté de Santé, Université de Paris, 4 avenue de l'Observatoire, 75006, Paris, France
| | - Fanchon Bourasset
- Laboratoire de Recherches Intégratives en Neurosciences et Psychologie Cognitive, Université Bourgogne Franche-Comté, 19 rue Ambroise Paré, 25000, Besançon, France.
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13
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Fuchsberger T, Yuste R, Martinez-Bellver S, Blanco-Gandia MC, Torres-Cuevas I, Blasco-Serra A, Arango R, Miñarro J, Rodríguez-Arias M, Teruel-Marti V, Lloret A, Viña J. Oral Monosodium Glutamate Administration Causes Early Onset of Alzheimer's Disease-Like Pathophysiology in APP/PS1 Mice. J Alzheimers Dis 2020; 72:957-975. [PMID: 31658055 DOI: 10.3233/jad-190274] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Glutamate excitotoxicity has long been related to Alzheimer's disease (AD) pathophysiology, and it has been shown to affect the major AD-related hallmarks, amyloid-β peptide (Aβ) accumulation and tau phosphorylation (p-tau). We investigated whether oral administration of monosodium glutamate (MSG) has effects in a murine model of AD, the double transgenic mice APP/PS1. We found that AD pathogenic factors appear earlier in APP/PS1 when supplemented with MSG, while wildtype mice were essentially not affected. Aβ and p-tau levels were increased in the hippocampus in young APP/PS1 animals upon MSG administration. This was correlated with increased Cdk5-p25 levels. Furthermore, in these mice, we observed a decrease in the AMPA receptor subunit GluA1 and they had impaired long-term potentiation. The Hebb-Williams Maze revealed that they had memory deficits. We show here for the first time that oral MSG supplementation can accelerate AD-like pathophysiology in a mouse model of AD.
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Affiliation(s)
- Tanja Fuchsberger
- Department of Physiology, Faculty of Medicine, Universitat de València, Valencia, Spain
| | - Raquel Yuste
- Department of Physiology, Faculty of Medicine, Universitat de València, Valencia, Spain
| | - Sergio Martinez-Bellver
- Department of Anatomy and Human Embriology, Faculty of Medicine, Universitat de València, Valencia, Spain
| | | | | | - Arantxa Blasco-Serra
- Department of Anatomy and Human Embriology, Faculty of Medicine, Universitat de València, Valencia, Spain
| | - Román Arango
- Department of Anatomy and Human Embriology, Faculty of Medicine, Universitat de València, Valencia, Spain.,Department of Computer Science, School of Engineering ETSE, Universitat de València, Burjassot, Spain
| | - Jose Miñarro
- Department of Psychobiology, Faculty of Psycology, Universitat de València, Valencia, Spain
| | - Marta Rodríguez-Arias
- Department of Psychobiology, Faculty of Psycology, Universitat de València, Valencia, Spain
| | - Vicent Teruel-Marti
- Department of Anatomy and Human Embriology, Faculty of Medicine, Universitat de València, Valencia, Spain
| | - Ana Lloret
- Department of Physiology, Faculty of Medicine, Universitat de València, Valencia, Spain
| | - Jose Viña
- Department of Physiology, Faculty of Medicine, Universitat de València, Valencia, Spain
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14
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Swaminathan SK, Zhou AL, Ahlschwede KM, Curran GL, Lowe VJ, Li L, Kandimalla KK. High-Density Lipoprotein Mimetic Peptide 4F Efficiently Crosses the Blood-Brain Barrier and Modulates Amyloid- β Distribution between Brain and Plasma. J Pharmacol Exp Ther 2020; 375:308-316. [PMID: 32778535 PMCID: PMC7589947 DOI: 10.1124/jpet.120.265876] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 07/24/2020] [Indexed: 12/24/2022] Open
Abstract
Treatments to elevate high-density lipoprotein (HDL) levels in plasma have decreased cerebrovascular amyloid -β (Aβ) deposition and mitigated cognitive decline in Alzheimer disease (AD) transgenic mice. Since the major protein component of HDL particles, apolipoprotein A-I (ApoA-I), has very low permeability at the blood-brain barrier (BBB), we investigated 4F, an 18-amino-acid ApoA-I/HDL mimetic peptide, as a therapeutic alternative. Specifically, we examined the BBB permeability of 4F and its effects on [125I]Aβ trafficking from brain to blood and from blood to brain. After systemic injection in mice, the BBB permeability of [125I]4F, estimated as the permeability-surface area (PS) product, ranged between 2 and 5 × 10-6 ml/g per second in various brain regions. The PS products of [125I]4F were ∼1000-fold higher compared with those determined for [125I]ApoA-I. Moreover, systemic infusion with 4F increased the brain efflux of intracerebrally injected [125I]Aβ42. Conversely, 4F infusion decreased the brain influx of systemically injected [125I]Aβ42. Interestingly, 4F did not significantly alter the brain influx of [125I]Aβ40. To corroborate the in vivo findings, we evaluated the effects of 4F on [125I]Aβ42 transcytosis across polarized human BBB endothelial cell (hCMEC/D3) monolayers. Treatment with 4F increased the abluminal-to-luminal flux and decreased the luminal-to-abluminal flux of [125I]Aβ42 across the hCMEC/D3 monolayers. Additionally, 4F decreased the endothelial accumulation of fluorescein-labeled Aβ42 in the hCMEC/D3 monolayers. These findings provide a mechanistic interpretation for the reductions in brain Aβ burden reported in AD mice after oral 4F administration, which represents a novel strategy for treating AD and cerebral amyloid angiopathy. SIGNIFICANCE STATEMENT: The brain permeability of the ApoA-I mimetic peptide 4F was estimated to be ∼1000-fold greater than ApoA-I after systemic injection of radiolabeled peptide/protein in mice. Further, 4F treatment increased the brain efflux of amyloid -β and also decreased its brain influx, as evaluated in mice and in blood-brain barrier cell monolayers. Thus, 4F represents a potential therapeutic strategy to mitigate brain amyloid accumulation in cerebral amyloid angiopathy and Alzheimer disease.
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Affiliation(s)
- Suresh K Swaminathan
- Department of Pharmaceutics and Brain Barriers Research Center (S.K.S., A.L.Z., K.M.A., K.K.K.) and Department of Experimental and Clinical Pharmacology (L.L.), University of Minnesota, College of Pharmacy, Minneapolis, Minnesota; Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (K.M.A.); and Departments of Radiology (G.L.C., V.J.L.) and Neurology (G.L.C.), Mayo Clinic, College of Medicine, Rochester, Minnesota
| | - Andrew L Zhou
- Department of Pharmaceutics and Brain Barriers Research Center (S.K.S., A.L.Z., K.M.A., K.K.K.) and Department of Experimental and Clinical Pharmacology (L.L.), University of Minnesota, College of Pharmacy, Minneapolis, Minnesota; Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (K.M.A.); and Departments of Radiology (G.L.C., V.J.L.) and Neurology (G.L.C.), Mayo Clinic, College of Medicine, Rochester, Minnesota
| | - Kristen M Ahlschwede
- Department of Pharmaceutics and Brain Barriers Research Center (S.K.S., A.L.Z., K.M.A., K.K.K.) and Department of Experimental and Clinical Pharmacology (L.L.), University of Minnesota, College of Pharmacy, Minneapolis, Minnesota; Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (K.M.A.); and Departments of Radiology (G.L.C., V.J.L.) and Neurology (G.L.C.), Mayo Clinic, College of Medicine, Rochester, Minnesota
| | - Geoffry L Curran
- Department of Pharmaceutics and Brain Barriers Research Center (S.K.S., A.L.Z., K.M.A., K.K.K.) and Department of Experimental and Clinical Pharmacology (L.L.), University of Minnesota, College of Pharmacy, Minneapolis, Minnesota; Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (K.M.A.); and Departments of Radiology (G.L.C., V.J.L.) and Neurology (G.L.C.), Mayo Clinic, College of Medicine, Rochester, Minnesota
| | - Val J Lowe
- Department of Pharmaceutics and Brain Barriers Research Center (S.K.S., A.L.Z., K.M.A., K.K.K.) and Department of Experimental and Clinical Pharmacology (L.L.), University of Minnesota, College of Pharmacy, Minneapolis, Minnesota; Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (K.M.A.); and Departments of Radiology (G.L.C., V.J.L.) and Neurology (G.L.C.), Mayo Clinic, College of Medicine, Rochester, Minnesota
| | - Ling Li
- Department of Pharmaceutics and Brain Barriers Research Center (S.K.S., A.L.Z., K.M.A., K.K.K.) and Department of Experimental and Clinical Pharmacology (L.L.), University of Minnesota, College of Pharmacy, Minneapolis, Minnesota; Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (K.M.A.); and Departments of Radiology (G.L.C., V.J.L.) and Neurology (G.L.C.), Mayo Clinic, College of Medicine, Rochester, Minnesota
| | - Karunya K Kandimalla
- Department of Pharmaceutics and Brain Barriers Research Center (S.K.S., A.L.Z., K.M.A., K.K.K.) and Department of Experimental and Clinical Pharmacology (L.L.), University of Minnesota, College of Pharmacy, Minneapolis, Minnesota; Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois (K.M.A.); and Departments of Radiology (G.L.C., V.J.L.) and Neurology (G.L.C.), Mayo Clinic, College of Medicine, Rochester, Minnesota
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15
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Munji RN, Daneman R. Unexpected amount of blood-borne protein enters the young brain. Nature 2020; 583:362-363. [DOI: 10.1038/d41586-020-01791-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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16
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Ulanova M, Poljak A, Wen W, Bongers A, Gloag L, Gooding J, Tilley R, Sachdev P, Braidy N. Nanoparticles as contrast agents for the diagnosis of Alzheimer’s disease: a systematic review. Nanomedicine (Lond) 2020; 15:725-743. [DOI: 10.2217/nnm-2019-0316] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Nanoparticle (NP)-based magnetic contrast agents have opened the potential for MRI to be used for early diagnosis of Alzheimer’s disease (AD). This article aims to review the current progress of research in this field. A comprehensive literature search was performed based on PubMed, Medline, EMBASE, PsychINFO and Scopus databases using the following terms: ‘Alzheimer’s disease’ AND ‘nanoparticles’ AND ‘Magnetic Resonance Imaging.’ 33 studies were included that described the development and utility of various NPs for AD imaging, including their coating, functionalization, MRI relaxivity, toxicity and bioavailability. NPs show immense promise for neuroimaging, due to superior relaxivity and biocompatibility compared with currently available imaging agents. Consistent reporting is imperative for further progress in this field.
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Affiliation(s)
- Marina Ulanova
- Centre for Healthy Brain Ageing, School of Psychiatry, The University of New South Wales, Sydney, NSW, 2052, Australia
| | - Anne Poljak
- Centre for Healthy Brain Ageing, School of Psychiatry, The University of New South Wales, Sydney, NSW, 2052, Australia
- Mark Wainwright Analytical Centre, The University of New South Wales, Sydney, NSW, 2052, Australia
- School of Medical Sciences, The University of New South Wales, Sydney, NSW, 2052, Australia
| | - Wei Wen
- Centre for Healthy Brain Ageing, School of Psychiatry, The University of New South Wales, Sydney, NSW, 2052, Australia
| | - Andre Bongers
- Mark Wainwright Analytical Centre, The University of New South Wales, Sydney, NSW, 2052, Australia
- Biological Resources Imaging Laboratory, Mark Wainwright Analytical Centre, The University of New South Wales, Sydney, NSW, 2052, Australia
| | - Lucy Gloag
- School of Chemistry, The University of New South Wales, Sydney, NSW, 2052, Australia
- Australian Centre for NanoMedicine, The University of New South Wales, Sydney, NSW, 2052, Australia
| | - Justin Gooding
- School of Chemistry, The University of New South Wales, Sydney, NSW, 2052, Australia
- Australian Centre for NanoMedicine, The University of New South Wales, Sydney, NSW, 2052, Australia
- ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, The University of New South Wales, Sydney, NSW, 2052, Australia
| | - Richard Tilley
- Mark Wainwright Analytical Centre, The University of New South Wales, Sydney, NSW, 2052, Australia
- School of Chemistry, The University of New South Wales, Sydney, NSW, 2052, Australia
- Australian Centre for NanoMedicine, The University of New South Wales, Sydney, NSW, 2052, Australia
| | - Perminder Sachdev
- Centre for Healthy Brain Ageing, School of Psychiatry, The University of New South Wales, Sydney, NSW, 2052, Australia
- Neuropsychiatric Institute, Euroa Centre, Prince of Wales Hospital, Sydney, NSW, 2052, Australia
| | - Nady Braidy
- Centre for Healthy Brain Ageing, School of Psychiatry, The University of New South Wales, Sydney, NSW, 2052, Australia
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17
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Costea L, Mészáros Á, Bauer H, Bauer HC, Traweger A, Wilhelm I, Farkas AE, Krizbai IA. The Blood-Brain Barrier and Its Intercellular Junctions in Age-Related Brain Disorders. Int J Mol Sci 2019; 20:ijms20215472. [PMID: 31684130 PMCID: PMC6862160 DOI: 10.3390/ijms20215472] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Revised: 10/30/2019] [Accepted: 11/01/2019] [Indexed: 12/14/2022] Open
Abstract
With age, our cognitive skills and abilities decline. Maybe starting as an annoyance, this decline can become a major impediment to normal daily life. Recent research shows that the neurodegenerative disorders responsible for age associated cognitive dysfunction are mechanistically linked to the state of the microvasculature in the brain. When the microvasculature does not function properly, ischemia, hypoxia, oxidative stress and related pathologic processes ensue, further damaging vascular and neural function. One of the most important and specialized functions of the brain microvasculature is the blood-brain barrier (BBB), which controls the movement of molecules between blood circulation and the brain parenchyma. In this review, we are focusing on tight junctions (TJs), the multiprotein complexes that play an important role in establishing and maintaining barrier function. After a short introduction of the cell types that modulate barrier function via intercellular communication, we examine how age, age related pathologies and the aging of the immune system affects TJs. Then, we review how the TJs are affected in age associated neurodegenerative disorders: Alzheimer's disease and Parkinson's disease. Lastly, we summarize the TJ aspects of Huntington's disease and schizophrenia. Barrier dysfunction appears to be a common denominator in neurological disorders, warranting detailed research into the molecular mechanisms behind it. Learning the commonalities and differences in the pathomechanism of the BBB injury in different neurological disorders will predictably lead to development of new therapeutics that improve our life as we age.
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Affiliation(s)
- Laura Costea
- Institute of Life Sciences, Vasile Goldiş Western University of Arad, 310414 Arad, Romania.
| | - Ádám Mészáros
- Institute of Biophysics, Biological Research Centre, 6726 Szeged, Hungary.
- Doctoral School of Biology, University of Szeged, 6726 Szeged, Hungary.
| | - Hannelore Bauer
- Department of Biological Sciences, University of Salzburg, 5020 Salzburg, Austria.
| | - Hans-Christian Bauer
- Institute of Tendon and Bone Regeneration, Paracelsus Medical University-Spinal Cord Injury and Tissue Regeneration Center Salzburg, 5020 Salzburg, Austria.
| | - Andreas Traweger
- Institute of Tendon and Bone Regeneration, Paracelsus Medical University-Spinal Cord Injury and Tissue Regeneration Center Salzburg, 5020 Salzburg, Austria.
| | - Imola Wilhelm
- Institute of Life Sciences, Vasile Goldiş Western University of Arad, 310414 Arad, Romania.
- Institute of Biophysics, Biological Research Centre, 6726 Szeged, Hungary.
| | - Attila E Farkas
- Institute of Biophysics, Biological Research Centre, 6726 Szeged, Hungary.
- Department of Physiology, Anatomy and Neuroscience, University of Szeged, 6726 Szeged, Hungary.
| | - István A Krizbai
- Institute of Life Sciences, Vasile Goldiş Western University of Arad, 310414 Arad, Romania.
- Institute of Biophysics, Biological Research Centre, 6726 Szeged, Hungary.
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18
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Rhea EM, Banks WA. Role of the Blood-Brain Barrier in Central Nervous System Insulin Resistance. Front Neurosci 2019; 13:521. [PMID: 31213970 PMCID: PMC6558081 DOI: 10.3389/fnins.2019.00521] [Citation(s) in RCA: 153] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 05/06/2019] [Indexed: 01/01/2023] Open
Abstract
The blood-brain barrier (BBB) mediates the communication between the periphery and the central nervous system (CNS). Recently, CNS insulin resistance has been elucidated to play a role in neurodegenerative disease. This has stimulated a wealth of information on the molecular impact of insulin in the brain, particularly in the improvement of cognition. Since the BBB regulates the transport of insulin into the brain and thus, helps to regulate CNS levels, alterations in the BBB response to insulin could impact CNS insulin resistance. In this review, we summarize the effect of insulin on some of the cell types that make up the BBB, including endothelial cells, neurons, astrocytes, and pericytes. We broadly discuss how these changes in specific cell types could ultimately impact the BBB. We also summarize how insulin can regulate levels of the pathological hallmarks of Alzheimer's disease, including amyloid beta (Aβ) and tau within each cell type. Finally, we suggest interventional approaches to overcome detrimental effects on the BBB in regards to changes in insulin transport.
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Affiliation(s)
- Elizabeth M Rhea
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States.,Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, United States
| | - William A Banks
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States.,Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, United States
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19
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Zhou AL, Swaminathan SK, Curran GL, Poduslo JF, Lowe VJ, Li L, Kandimalla KK. Apolipoprotein A-I Crosses the Blood-Brain Barrier through Clathrin-Independent and Cholesterol-Mediated Endocytosis. J Pharmacol Exp Ther 2019; 369:481-488. [PMID: 30971477 PMCID: PMC6538888 DOI: 10.1124/jpet.118.254201] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 03/11/2019] [Indexed: 11/22/2022] Open
Abstract
Recent studies suggest that apolipoprotein A-I (ApoA-I), the major protein constituent of high-density lipoprotein particles, plays a critical role in preserving cerebrovascular integrity and reducing Alzheimer's risk. ApoA-I present in brain is thought to be primarily derived from the peripheral circulation. Although plasma-to-brain delivery of ApoA-I is claimed to be handled by the blood-cerebrospinal fluid barrier (BCSFB), a contribution by the blood-brain barrier (BBB), which serves as a major portal for protein delivery to brain, cannot be ruled out. In this study, we assessed the permeability-surface area product (PS) of radioiodinated ApoA-I (125I-ApoA-I) in various brain regions of wild-type rats after an intravenous bolus injection. The PS value at the cortex, caudate putamen, hippocampus, thalamus, brain stem, and cerebellum was found to be 0.39, 0.28, 0.28, 0.36, 0.69, and 0.76 (ml/g per second × 10-6), respectively. Solutes delivered into brain via the BCSFB are expected to show greater accumulation in the thalamus due to its periventricular location. The modest permeability for 125I-ApoA-I into the thalamus relative to other regions suggests that BCSFB transport accounts for only a portion of total brain uptake and thus BBB transport cannot be ruled out. In addition, we show that Alexa Flour 647-labeled ApoA-I (AF647-ApoA-I) undergoes clathrin-independent and cholesterol-mediated endocytosis in transformed human cerebral microvascular endothelial cells (hCMEC/D3). Further, Z-series confocal images of the hCMEC/D3 monolayers and Western blot detection of intact ApoA-I on the abluminal side demonstrated AF647-ApoA-I transcytosis across the endothelium. These findings implicate the BBB as a significant portal for ApoA-I delivery into brain.
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Affiliation(s)
- Andrew L Zhou
- Department of Pharmaceutics and Brain Barriers Research Center (A.L.Z., S.K.S., K.K.K.) and Department of Experimental and Clinical Pharmacology (L.L.), College of Pharmacy, University of Minnesota, Minneapolis, Minnesota; and Department of Radiology (G.L.C., V.J.L.) and Department of Neurology (G.L.C., J.F.P.), Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Suresh K Swaminathan
- Department of Pharmaceutics and Brain Barriers Research Center (A.L.Z., S.K.S., K.K.K.) and Department of Experimental and Clinical Pharmacology (L.L.), College of Pharmacy, University of Minnesota, Minneapolis, Minnesota; and Department of Radiology (G.L.C., V.J.L.) and Department of Neurology (G.L.C., J.F.P.), Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Geoffry L Curran
- Department of Pharmaceutics and Brain Barriers Research Center (A.L.Z., S.K.S., K.K.K.) and Department of Experimental and Clinical Pharmacology (L.L.), College of Pharmacy, University of Minnesota, Minneapolis, Minnesota; and Department of Radiology (G.L.C., V.J.L.) and Department of Neurology (G.L.C., J.F.P.), Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Joseph F Poduslo
- Department of Pharmaceutics and Brain Barriers Research Center (A.L.Z., S.K.S., K.K.K.) and Department of Experimental and Clinical Pharmacology (L.L.), College of Pharmacy, University of Minnesota, Minneapolis, Minnesota; and Department of Radiology (G.L.C., V.J.L.) and Department of Neurology (G.L.C., J.F.P.), Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Val J Lowe
- Department of Pharmaceutics and Brain Barriers Research Center (A.L.Z., S.K.S., K.K.K.) and Department of Experimental and Clinical Pharmacology (L.L.), College of Pharmacy, University of Minnesota, Minneapolis, Minnesota; and Department of Radiology (G.L.C., V.J.L.) and Department of Neurology (G.L.C., J.F.P.), Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Ling Li
- Department of Pharmaceutics and Brain Barriers Research Center (A.L.Z., S.K.S., K.K.K.) and Department of Experimental and Clinical Pharmacology (L.L.), College of Pharmacy, University of Minnesota, Minneapolis, Minnesota; and Department of Radiology (G.L.C., V.J.L.) and Department of Neurology (G.L.C., J.F.P.), Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Karunya K Kandimalla
- Department of Pharmaceutics and Brain Barriers Research Center (A.L.Z., S.K.S., K.K.K.) and Department of Experimental and Clinical Pharmacology (L.L.), College of Pharmacy, University of Minnesota, Minneapolis, Minnesota; and Department of Radiology (G.L.C., V.J.L.) and Department of Neurology (G.L.C., J.F.P.), Mayo Clinic College of Medicine, Rochester, Minnesota
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20
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Saeedi M, Eslamifar M, Khezri K, Dizaj SM. Applications of nanotechnology in drug delivery to the central nervous system. Biomed Pharmacother 2019; 111:666-675. [PMID: 30611991 DOI: 10.1016/j.biopha.2018.12.133] [Citation(s) in RCA: 189] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 12/21/2018] [Accepted: 12/30/2018] [Indexed: 12/31/2022] Open
Abstract
In recent years, the researchers and drug designers have given growing attention to new nanotechnology strategies to improve drug delivery to the central nervous system (CNS). Nanotechnology has a great potential to affect the treatment of neurological disorders, mainly Alzheimer's disease, Parkinson's disease, brain tumors, and stroke. With regard to neurodegeneration, several studies showed that nanomaterials have been successfully used for the treatments of CNS disorders. In this regard, nanocarriers have facilitated the targeted delivery of chemotherapeutics resulting in the efficient inhibition of disease progression in malignant brain tumors. Therefore, the most efficacious application of nanomaterials is the use of these substances in the treatment of CNS disease that enhances the overall effect of drug and highlights the importance of nano-therapeutics. This study was conducted to review the evidence on the applications of nanotechnology in designing drug delivery systems with the ability to cross through the blood-brain barrier (BBB) in order to transfer the therapeutic agents to the CNS.
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Affiliation(s)
- Majid Saeedi
- Department of Pharmaceutics, Faculty of Pharmacy, Mazandaran University of Medical Science, Sari, Iran
| | - Masoumeh Eslamifar
- Department of Environmental Health Engineering, Faculty of Health, Mazandaran University of Medical Science, Sari, Iran.
| | - Khadijeh Khezri
- Student Research Committee, Department of Pharmaceutics, Faculty of Pharmacy, Mazandaran University of Medical Science, Sari, Iran..
| | - Solmaz Maleki Dizaj
- Dental and Periodontal Research Center and Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
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21
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Carvalho C, Cardoso SM, Correia SC, Moreira PI. Tortuous Paths of Insulin Signaling and Mitochondria in Alzheimer's Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1128:161-183. [PMID: 31062330 DOI: 10.1007/978-981-13-3540-2_9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Due to the exponential growth of aging population worldwide, neurodegenerative diseases became a major public health concern. Among them, Alzheimer's disease (AD) prevails as the most common in the elderly, rendering it a research priority. After several decades considering the brain as an insulin-insensitive organ, recent advances proved a central role for this hormone in learning and memory processes and showed that AD shares a high number of features with systemic conditions characterized by insulin resistance. Mitochondrial dysfunction has also been widely demonstrated to play a major role in AD development supporting the idea that this neurodegenerative disease is characterized by a pronounced metabolic dysregulation. This chapter is intended to discuss evidence demonstrating the key role of insulin signaling and mitochondrial anomalies in AD.
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Affiliation(s)
- Cristina Carvalho
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal
| | - Susana M Cardoso
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal
| | - Sónia C Correia
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal
| | - Paula I Moreira
- CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal. .,Laboratory of Physiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
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22
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In Vitro Cell Models of the Human Blood-Brain Barrier: Demonstrating the Beneficial Influence of Shear Stress on Brain Microvascular Endothelial Cell Phenotype. ACTA ACUST UNITED AC 2018. [DOI: 10.1007/978-1-4939-8946-1_5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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23
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Rhea EM, Salameh TS, Banks WA. Routes for the delivery of insulin to the central nervous system: A comparative review. Exp Neurol 2018; 313:10-15. [PMID: 30500332 DOI: 10.1016/j.expneurol.2018.11.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 11/18/2018] [Accepted: 11/24/2018] [Indexed: 12/15/2022]
Abstract
Central nervous system (CNS) insulin resistance is a condition in which the cells within the CNS do not respond to insulin appropriately and is often linked to aberrant CNS insulin levels. CNS insulin is primarily derived from the periphery. Aberrant CNS insulin levels can arise due to various factors including i) decreased endogenous insulin transport into the brain, across the blood-brain barrier (BBB), ii) reduced CNS sequestration of insulin, and iii) increased CNS degradation. While the sole route of endogenous insulin transport into the brain is via the BBB, there are multiple therapeutic routes of administration that have been investigated to deliver exogenous insulin to the CNS. These alternative administrative routes can be utilized to increase the amount of CNS insulin and aid in overcoming CNS insulin resistance. This review focuses on the intravenous, intracerebroventricular, intranasal, ocular, and intrathecal routes of administration and compares the impact of insulin delivery.
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Affiliation(s)
- Elizabeth M Rhea
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Therese S Salameh
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, USA
| | - William A Banks
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA, USA.
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24
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Ahlschwede KM, Curran GL, Rosenberg JT, Grant SC, Sarkar G, Jenkins RB, Ramakrishnan S, Poduslo JF, Kandimalla KK. Cationic carrier peptide enhances cerebrovascular targeting of nanoparticles in Alzheimer's disease brain. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2018; 16:258-266. [PMID: 30300748 DOI: 10.1016/j.nano.2018.09.010] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 09/02/2018] [Accepted: 09/13/2018] [Indexed: 11/18/2022]
Abstract
Accumulation of amyloid beta (Aβ) peptides in the cerebral vasculature, referred to as cerebral amyloid angiopathy (CAA), is widely observed in Alzheimer's disease (AD) brain and was shown to accelerate cognitive decline. There is no effective method for detecting cerebrovascular amyloid (CVA) and treat CAA. The targeted nanoparticles developed in this study effectively migrated from the blood flow to the vascular endothelium as determined by using quartz crystal microbalance with dissipation monitoring (QCM-D) technology. We also improved the stability, and blood-brain barrier (BBB) transcytosis of targeted nanoparticles by coating them with a cationic BBB penetrating peptide (K16ApoE). The K16ApoE-Targeted nanoparticles demonstrated specific targeting of vasculotropic DutchAβ40 peptide accumulated in the cerebral vasculature. Moreover, K16ApoE-Targeted nanoparticles demonstrated significantly greater uptake into brain and provided specific MRI contrast to detect brain amyloid plaques.
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Affiliation(s)
- Kristen M Ahlschwede
- Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA; Molecular Neurobiology Laboratory, Departments of Neurology, Neuroscience and Biochemistry/Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA; Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
| | - Geoffry L Curran
- Molecular Neurobiology Laboratory, Departments of Neurology, Neuroscience and Biochemistry/Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Jens T Rosenberg
- The National High Magnetic Field Laboratory, Florida State University, Tallahassee, FL, USA; Department of Chemical & Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL, USA
| | - Samuel C Grant
- The National High Magnetic Field Laboratory, Florida State University, Tallahassee, FL, USA; Department of Chemical & Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL, USA
| | - Gobinda Sarkar
- Department of Experimental Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Robert B Jenkins
- Department of Experimental Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Subramanian Ramakrishnan
- The National High Magnetic Field Laboratory, Florida State University, Tallahassee, FL, USA; Department of Chemical & Biomedical Engineering, FAMU-FSU College of Engineering, Florida State University, Tallahassee, FL, USA
| | - Joseph F Poduslo
- Molecular Neurobiology Laboratory, Departments of Neurology, Neuroscience and Biochemistry/Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Karunya K Kandimalla
- Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA; Molecular Neurobiology Laboratory, Departments of Neurology, Neuroscience and Biochemistry/Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
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25
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Pan Y, Nicolazzo JA. Impact of aging, Alzheimer's disease and Parkinson's disease on the blood-brain barrier transport of therapeutics. Adv Drug Deliv Rev 2018; 135:62-74. [PMID: 29665383 DOI: 10.1016/j.addr.2018.04.009] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 01/17/2018] [Accepted: 04/07/2018] [Indexed: 01/01/2023]
Abstract
Older people are at a greater risk of medicine-induced toxicity resulting from either increased drug sensitivity or age-related pharmacokinetic changes. The scenario is further complicated with the two most prevalent age-related neurodegenerative diseases, Alzheimer's disease (AD) and Parkinson's disease (PD). With aging, AD and PD, there is growing evidence of altered structure and function of the blood-brain barrier (BBB), including modifications to tight junctions and efflux transporters, such as P-glycoprotein. The subsequent impact on CNS drug exposure and risk of neurotoxicity from systemically-acting medicines is less well characterized. The purpose of this review, therefore, is to provide an overview of the multiple changes that occur to the BBB as a result of aging, AD and PD, and the impact that such changes have on CNS exposure of drugs, based on studies conducted in aged rodents or rodent models of disease, and in elderly people with and without AD or PD.
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Affiliation(s)
- Yijun Pan
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, Parkville, Victoria 3052, Australia
| | - Joseph A Nicolazzo
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, Parkville, Victoria 3052, Australia.
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26
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Ott BR, Jones RN, Daiello LA, de la Monte SM, Stopa EG, Johanson CE, Denby C, Grammas P. Blood-Cerebrospinal Fluid Barrier Gradients in Mild Cognitive Impairment and Alzheimer's Disease: Relationship to Inflammatory Cytokines and Chemokines. Front Aging Neurosci 2018; 10:245. [PMID: 30186149 PMCID: PMC6110816 DOI: 10.3389/fnagi.2018.00245] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Accepted: 07/25/2018] [Indexed: 01/30/2023] Open
Abstract
Background: The pathophysiology underlying altered blood-cerebrospinal fluid barrier (BCSFB) function in Alzheimer's disease (AD) is unknown but may relate to endothelial cell activation and cytokine mediated inflammation. Methods: Cerebrospinal fluid (CSF) and peripheral blood were concurrently collected from cognitively healthy controls (N = 21) and patients with mild cognitive impairment (MCI) (N = 8) or AD (N = 11). The paired serum and CSF samples were assayed for a panel of cytokines, chemokines, and related trophic factors using multiplex ELISAs. Dominance analysis models were conducted to determine the relative importance of the inflammatory factors in relationship to BCSFB permeability, as measured by CSF/serum ratios for urea, creatinine, and albumin. Results: BCSFB disruption to urea, a small molecule distributed by passive diffusion, had a full model coefficient of determination (r2) = 0.35, and large standardized dominance weights (>0.1) for monocyte chemoattractant protein-1, interleukin (IL)-15, IL-1rα, and IL-2 in serum. BCSFB disruption to creatinine, a larger molecule governed by active transport, had a full model r2 = 0.78, and large standardized dominance weights for monocyte inhibitor protein-1b in CSF and tumor necrosis factor-α in serum. BCSFB disruption to albumin, a much larger molecule, had a full model r2 = 0.62, and large standardized dominance weights for IL-17a, interferon-gamma, IL-2, and VEGF in CSF, as well IL-4 in serum. Conclusions: Inflammatory proteins have been widely documented in the AD brain. The results of the current study suggest that changes in BCSFB function resulting in altered permeability and transport are related to expression of specific inflammatory proteins, and that the shifting distribution of these proteins from serum to CSF in AD and MCI is correlated with more severe perturbations in BCSFB function.
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Affiliation(s)
- Brian R. Ott
- Department of Neurology, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI, United States,George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI, United States,*Correspondence: Brian R. Ott
| | - Richard N. Jones
- Department of Neurology, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI, United States
| | - Lori A. Daiello
- Department of Neurology, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI, United States
| | - Suzanne M. de la Monte
- George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI, United States,Division of Neuropathology, Department of Pathology, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI, United States
| | - Edward G. Stopa
- George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI, United States,Division of Neuropathology, Department of Pathology, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI, United States
| | - Conrad E. Johanson
- Department of Neurosurgery, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI, United States
| | - Charles Denby
- Department of Neurology, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI, United States
| | - Paula Grammas
- George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI, United States
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27
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Swaminathan SK, Ahlschwede KM, Sarma V, Curran GL, Omtri RS, Decklever T, Lowe VJ, Poduslo JF, Kandimalla KK. Insulin differentially affects the distribution kinetics of amyloid beta 40 and 42 in plasma and brain. J Cereb Blood Flow Metab 2018; 38:904-918. [PMID: 28569090 PMCID: PMC5987944 DOI: 10.1177/0271678x17709709] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Impaired brain clearance of amyloid-beta peptides (Aβ) 40 and 42 across the blood-brain barrier (BBB) is believed to be one of the pathways responsible for Alzheimer's disease (AD) pathogenesis. Hyperinsulinemia prevalent in type II diabetes was shown to damage cerebral vasculature and increase Aβ accumulation in AD brain. However, there is no clarity on how aberrations in peripheral insulin levels affect Aβ accumulation in the brain. This study describes, for the first time, an intricate relation between plasma insulin and Aβ transport at the BBB. Upon peripheral insulin administration in wild-type mice: the plasma clearance of Aβ40 increased, but Aβ42 clearance reduced; the plasma-to-brain influx of Aβ40 increased, and that of Aβ42 reduced; and the clearance of intracerebrally injected Aβ40 decreased, whereas Aβ42 clearance increased. In hCMEC/D3 monolayers (in vitro BBB model) exposed to insulin, the luminal uptake and luminal-to-abluminal permeability of Aβ40 increased and that of Aβ42 reduced; the abluminal-to-luminal permeability of Aβ40 decreased, whereas Aβ42 permeability increased. Moreover, Aβ cellular trafficking machinery was altered. In summary, Aβ40 and Aβ42 demonstrated distinct distribution kinetics in plasma and brain compartments, and insulin differentially modulated their distribution. Cerebrovascular disease and metabolic disorders may disrupt this intricate homeostasis and aggravate AD pathology.
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Affiliation(s)
- Suresh Kumar Swaminathan
- 1 Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.,2 Department of Radiology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Kristen M Ahlschwede
- 1 Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.,3 Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Vidur Sarma
- 1 Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.,2 Department of Radiology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Geoffry L Curran
- 2 Department of Radiology, Mayo Clinic College of Medicine, Rochester, MN, USA.,3 Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Rajesh S Omtri
- 1 Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA
| | - Teresa Decklever
- 2 Department of Radiology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Val J Lowe
- 2 Department of Radiology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Joseph F Poduslo
- 3 Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Karunya K Kandimalla
- 1 Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.,3 Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, USA
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28
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Rodriguez-Rodriguez P, Sandebring-Matton A, Merino-Serrais P, Parrado-Fernandez C, Rabano A, Winblad B, Ávila J, Ferrer I, Cedazo-Minguez A. Tau hyperphosphorylation induces oligomeric insulin accumulation and insulin resistance in neurons. Brain 2017; 140:3269-3285. [PMID: 29053786 DOI: 10.1093/brain/awx256] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Accepted: 08/11/2017] [Indexed: 11/13/2022] Open
Abstract
Insulin signalling deficiencies and insulin resistance have been directly linked to the progression of neurodegenerative disorders like Alzheimer's disease. However, to date little is known about the underlying molecular mechanisms or insulin state and distribution in the brain under pathological conditions. Here, we report that insulin is accumulated and retained as oligomers in hyperphosphorylated tau-bearing neurons in Alzheimer's disease and in several of the most prevalent human tauopathies. The intraneuronal accumulation of insulin is directly dependent on tau hyperphosphorylation, and follows the tauopathy progression. Furthermore, cells accumulating insulin show signs of insulin resistance and decreased insulin receptor levels. These results suggest that insulin retention in hyperphosphorylated tau-bearing neurons is a causative factor for the insulin resistance observed in tauopathies, and describe a novel neuropathological concept with important therapeutic implications.
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Affiliation(s)
- Patricia Rodriguez-Rodriguez
- Karolinska Institutet, Center for Alzheimer Research, Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Stockholm, Sweden
| | - Anna Sandebring-Matton
- Karolinska Institutet, Center for Alzheimer Research, Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Stockholm, Sweden
| | - Paula Merino-Serrais
- Karolinska Institutet, Center for Alzheimer Research, Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Stockholm, Sweden
| | - Cristina Parrado-Fernandez
- Karolinska Institutet, Center for Alzheimer Research, Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Stockholm, Sweden
| | - Alberto Rabano
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Spain.,Fundación CIEN, Madrid, Spain
| | - Bengt Winblad
- Karolinska Institutet, Center for Alzheimer Research, Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Stockholm, Sweden
| | - Jesús Ávila
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Spain.,Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain
| | - Isidre Ferrer
- Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Spain.,Institut de Neuropatologia, Servei Anatomia Patologica, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, Hospitalet de Llobregat, Barcelona, Spain
| | - Angel Cedazo-Minguez
- Karolinska Institutet, Center for Alzheimer Research, Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Stockholm, Sweden
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29
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Desai BS, Monahan AJ, Carvey PM, Hendey B. Blood–Brain Barrier Pathology in Alzheimer's and Parkinson's Disease: Implications for Drug Therapy. Cell Transplant 2017; 16:285-99. [PMID: 17503739 DOI: 10.3727/000000007783464731] [Citation(s) in RCA: 233] [Impact Index Per Article: 29.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The blood–brain barrier (BBB) is a tightly regulated barrier in the central nervous system. Though the BBB is thought to be intact during neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's disease (PD), recent evidence argues otherwise. Dysfunction of the BBB may be involved in disease progression, eliciting of peripheral immune response, and, most importantly, altered drug efficacy. In this review, we will give a brief overview of the BBB, its components, and their functions. We will critically evaluate the current literature in AD and PD BBB pathology resulting from insult, neuroinflammation, and neurodegeneration. Specifically, we will discuss alterations in tight junction, transport and endothelial cell surface proteins, and vascular density changes, all of which result in altered permeability. Finally, we will discuss the implications of BBB dysfunction in current and future therapeutics. Developing a better appreciation of BBB dysfunction in AD and PD may not only provide novel strategies in treatment, but will prove an interesting milestone in understanding neurodegenerative disease etiology and progression.
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Affiliation(s)
- Brinda S Desai
- Department of Pharmacology, Rush University Medical Center, Chicago, IL 60612, USA.
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30
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Asgari M, de Zélicourt DA, Kurtcuoglu V. Barrier dysfunction or drainage reduction: differentiating causes of CSF protein increase. Fluids Barriers CNS 2017; 14:14. [PMID: 28521764 PMCID: PMC5437537 DOI: 10.1186/s12987-017-0063-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Accepted: 05/09/2017] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Cerebrospinal fluid (CSF) protein analysis is an important element in the diagnostic chain for various central nervous system (CNS) pathologies. Among multiple existing approaches to interpreting measured protein levels, the Reiber diagram is particularly robust with respect to physiologic inter-individual variability, as it uses multiple subject-specific anchoring values. Beyond reliable identification of abnormal protein levels, the Reiber diagram has the potential to elucidate their pathophysiologic origin. In particular, both reduction of CSF drainage from the cranio-spinal space as well as blood-CNS barrier dysfunction have been suggested ρas possible causes of increased concentration of blood-derived proteins. However, there is disagreement on which of the two is the true cause. METHODS We designed two computational models to investigate the mechanisms governing protein distribution in the spinal CSF. With a one-dimensional model, we evaluated the distribution of albumin and immunoglobulin G (IgG), accounting for protein transport rates across blood-CNS barriers, CSF dynamics (including both dispersion induced by CSF pulsations and advection by mean CSF flow) and CSF drainage. Dispersion coefficients were determined a priori by computing the axisymmetric three-dimensional CSF dynamics and solute transport in a representative segment of the spinal canal. RESULTS Our models reproduce the empirically determined hyperbolic relation between albumin and IgG quotients. They indicate that variation in CSF drainage would yield a linear rather than the expected hyperbolic profile. In contrast, modelled barrier dysfunction reproduces the experimentally observed relation. CONCLUSIONS High levels of albumin identified in the Reiber diagram are more likely to originate from a barrier dysfunction than from a reduction in CSF drainage. Our in silico experiments further support the hypothesis of decreasing spinal CSF drainage in rostro-caudal direction and emphasize the physiological importance of pulsation-driven dispersion for the transport of large molecules in the CSF.
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Affiliation(s)
- Mahdi Asgari
- The Interface Group, Institute of Physiology, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.,Neuroscience Center Zurich, University of Zurich, Zurich, Switzerland
| | - Diane A de Zélicourt
- The Interface Group, Institute of Physiology, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland
| | - Vartan Kurtcuoglu
- The Interface Group, Institute of Physiology, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland. .,Neuroscience Center Zurich, University of Zurich, Zurich, Switzerland. .,Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
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31
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McInerney MP, Short JL, Nicolazzo JA. Neurovascular Alterations in Alzheimer's Disease: Transporter Expression Profiles and CNS Drug Access. AAPS JOURNAL 2017; 19:940-956. [PMID: 28462473 DOI: 10.1208/s12248-017-0077-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Accepted: 03/15/2017] [Indexed: 01/05/2023]
Abstract
Despite a century of steady and incremental progress toward understanding the underlying biochemical mechanisms, Alzheimer's disease (AD) remains a complicated and enigmatic disease, and greater insight will be necessary before substantive clinical success is realised. Over the last decade in particular, a large body of work has highlighted the cerebral microvasculature as an anatomical region with an increasingly apparent role in the pathogenesis of AD. The causative interplay and temporal cascade that manifest between the brain vasculature and the wider disease progression of AD are not yet fully understood, and further inquiry is required to properly characterise these relationships. The purpose of this review is to highlight the recent advancements in research implicating neurovascular factors in AD, at both the molecular and anatomical levels. We begin with a brief introduction of the biochemical and genetic aspects of AD, before reviewing the essential concepts of the blood-brain barrier (BBB) and the neurovascular unit (NVU). In detail, we then examine the evidence demonstrating involvement of BBB dysfunction in AD pathogenesis, highlighting the importance of neurovascular components in AD. Lastly, we include within this review research that focuses on how altered properties of the BBB in AD impact upon CNS exposure of therapeutic agents and the potential clinical impact that this may have on people with this disease.
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Affiliation(s)
- Mitchell P McInerney
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia
| | - Jennifer L Short
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, VIC, Australia
| | - Joseph A Nicolazzo
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia.
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Löffler T, Flunkert S, Temmel M, Hutter-Paier B. Decreased Plasma Aβ in Hyperlipidemic APPSL Transgenic Mice Is Associated with BBB Dysfunction. Front Neurosci 2016; 10:232. [PMID: 27313503 PMCID: PMC4887499 DOI: 10.3389/fnins.2016.00232] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2016] [Accepted: 05/10/2016] [Indexed: 11/13/2022] Open
Abstract
Besides the continued focus on Aβ and Tau in Alzheimer's disease (AD), it is increasingly evident that other pathologic characteristics, such as vascular alterations or inflammation, are associated with AD. Whether these changes are an initial cause for the onset of AD or occur as a result of the disease in late stages is still under debate. In the present study, the impact of the high-fat diet (HFD) induced vascular risk factor hyperlipidemia on Aβ levels and clearance as well as cerebral vasculature and blood-brain barrier (BBB) integrity was examined in mice. For this purpose, human APP transgenic (APPSL) and wildtype (WT) mice were fed a HFD for 12 weeks. Plasma and tissues were subsequently investigated for Aβ distribution and concentrations of several vascular markers. Decreased plasma Aβ together with increased levels of insoluble Aβ and amyloid plaques in the brains of HFD fed APPSL mice point toward impaired Aβ clearance due to HFD. Additionally, HFD induced manifold alterations in the cerebral vasculature and BBB integrity exclusively in human APP overexpressing mice but not in wildtype mice. Therefore, HFD appears to enhance Aβ dependent vascular/BBB dysfunction in combination with an increased proportion of cerebral to plasma Aβ in APPSL mice.
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Affiliation(s)
- Tina Löffler
- Neuropharmacology, QPS Austria Grambach, Austria
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Intra-Arterially Delivered Mesenchymal Stem Cells Are Not Detected in the Brain Parenchyma in an Alzheimer's Disease Mouse Model. PLoS One 2016; 11:e0155912. [PMID: 27203695 PMCID: PMC4874686 DOI: 10.1371/journal.pone.0155912] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Accepted: 05/08/2016] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have a promising role as a therapeutic agent for neurodegenerative diseases such as Alzheimer’s disease (AD). Prior studies suggested that intra-arterially administered MSCs are engrafted into the brain in stroke or traumatic brain injury (TBI) animal models. However, a controversial standpoint exists in terms of the integrity of the blood brain barrier (BBB) in transgenic AD mice. The primary goal of this study was to explore the feasibility of delivering human umbilical cord-blood derived mesenchymal stem cells (hUCB-MSCs) into the brains of non-transgenic WT (C3H/C57) and transgenic AD (APP/PS1) mice through the intra-arterial (IA) route. Through two experiments, mice were infused with hUCB-MSCs via the right internal carotid artery and were sacrificed at two different time points: 6 hours (experiment 1) or 5 minutes (experiment 2) after infusion. In both experiments, no cells were detected in the brain parenchyma while MSCs were detected in the cerebrovasculature in experiment 2. The results from this study highlight that intra-arterial delivery of MSCs is not the most favorable route to be implemented as a potential therapeutic approach for AD.
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A designed recombinant fusion protein for targeted delivery of siRNA to the mouse brain. J Control Release 2016; 228:120-131. [DOI: 10.1016/j.jconrel.2016.03.007] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Revised: 01/31/2016] [Accepted: 03/03/2016] [Indexed: 12/22/2022]
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Hamel E, Royea J, Ongali B, Tong XK. Neurovascular and Cognitive failure in Alzheimer's Disease: Benefits of Cardiovascular Therapy. Cell Mol Neurobiol 2016; 36:219-32. [PMID: 26993506 PMCID: PMC11482419 DOI: 10.1007/s10571-015-0285-4] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Accepted: 10/06/2015] [Indexed: 12/19/2022]
Abstract
Alzheimer's disease (AD) is a multifactorial and multifaceted disease for which we currently have very little to offer since there is no curative therapy, with only limited disease-modifying drugs. Recent studies in AD mouse models that recapitulate the amyloid-β (Aβ) pathology converge to demonstrate that it is possible to salvage cerebrovascular function with a variety of drugs and, particularly, therapies used to treat cardiovascular diseases such as hypercholesterolemia and hypertension. These drugs can reestablish dilatory function mediated by various endothelial and smooth muscle ion channels as well as nitric oxide availability, benefits that result in normalized brain perfusion. These cerebrovascular benefits would favor brain perfusion, which may help maintain neuronal function and, possibly, delay cognitive failure. However, restoring cerebrovascular function in AD mouse models was not necessarily accompanied by rescue of cognitive deficits related to spatial learning and memory. The results with cardiovascular therapies rather suggest that drugs originally designed to treat cardiovascular diseases that concurrently restore cerebrovascular and cognitive function do so through their pleiotropic effects. Specifically, recent findings suggest that these drugs act directly on brain cells and neuronal pathways involved in memory formation, hence, working simultaneously albeit independently on neuronal and vascular targets. These findings may help select medications for patients with cardiovascular diseases at risk of developing AD with increasing age. Further, they may identify molecular targets for recovering memory pathways that bear potential for new therapeutic avenues.
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Affiliation(s)
- Edith Hamel
- Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, 3801 University Street, Suite 748, Montréal, QC, H3A 2B4, Canada.
| | - Jessika Royea
- Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, 3801 University Street, Suite 748, Montréal, QC, H3A 2B4, Canada
| | - Brice Ongali
- Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, 3801 University Street, Suite 748, Montréal, QC, H3A 2B4, Canada
| | - Xin-Kang Tong
- Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, 3801 University Street, Suite 748, Montréal, QC, H3A 2B4, Canada
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Mukaetova-Ladinska EB, Li M, Kalaria RN. tau protein, ischemic injury and vascular dementia. FUTURE NEUROLOGY 2015. [DOI: 10.2217/fnl.15.46] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Clinical, neuroimaging and neuropathological studies have confirmed overlap between Alzheimer's disease (AD) and vascular dementia (VaD). Classical neuropathological changes of AD (plaques and tangles) can be present in VaD. We review neuroimaging, biochemical and animal studies to consider the role of tau protein in ischemic injury and VaD pathogenesis. The evidence comes largely from transgenic animal studies that confirm that tau transgenes influence cerebral vasculature. Clinicobiochemical studies in the cerebrospinal fluid (CSF) have, similarly, confirmed alterations in both total and phosphorylated tau protein in VaD. These data suggest that tau protein not only serves as a potential diagnostic tool for differential diagnosis of VaD from other types of dementia, but may also be a therapeutic target in ischemic stroke.
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Affiliation(s)
| | - Mosi Li
- Centre for Neuroregeneration, University of Edinburgh, Edinburgh, EH16 4SB, UK
| | - Raj N Kalaria
- Institute of Neuroscience, Newcastle University, Campus for Ageing & Vitality, Newcastle upon Tyne, NE4 5PL, UK
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Huang FYJ, Lee TW, Chang CH, Chen LC, Hsu WH, Chang CW, Lo JM. Evaluation of 188Re-labeled PEGylated nanoliposome as a radionuclide therapeutic agent in an orthotopic glioma-bearing rat model. Int J Nanomedicine 2015; 10:463-73. [PMID: 25624760 PMCID: PMC4296959 DOI: 10.2147/ijn.s75955] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
PURPOSE In this study, the (188)Re-labeled PEGylated nanoliposome ((188)Re-liposome) was prepared and evaluated as a therapeutic agent for glioma. MATERIALS AND METHODS The reporter cell line, F98(luc) was prepared via Lentivector expression kit system and used to set up the orthotopic glioma-bearing rat model for non-invasive bioluminescent imaging. The maximum tolerated dose applicable in Fischer344 rats was explored via body weight monitoring of the rats after single intravenous injection of (188)Re-liposome with varying dosages before the treatment study. The OLINDA/EXM 1.1 software was utilized for estimating the radiation dosimetry. To assess the therapeutic efficacy, tumor-bearing rats were intravenously administered (188)Re-liposome or normal saline followed by monitoring of the tumor growth and animal survival time. In addition, the histopathological examinations of tumors were conducted on the (188)Re-liposome-treated rats. RESULTS By using bioluminescent imaging, the well-established reporter cell line (F98(luc)) showed a high relationship between cell number and its bioluminescent intensity (R(2)=0.99) in vitro; furthermore, it could also provide clear tumor imaging for monitoring tumor growth in vivo. The maximum tolerated dose of (188)Re-liposome in Fischer344 rats was estimated to be 333 MBq. According to the dosimetry results, higher equivalent doses were observed in spleen and kidneys while very less were in normal brain, red marrow, and thyroid. For therapeutic efficacy study, the progression of tumor growth in terms of tumor volume and/or tumor weight was significantly slower for the (188)Re-liposome-treated group than the control group (P<0.05). As a result, the lifespan of glioma-bearing rats treated with (188)Re-liposome was prolonged 10.67% compared to the control group. CONCLUSION The radiotherapeutic evaluation by dosimetry and survival studies have demonstrated that passive targeting (188)Re-liposome via systemic administration can significantly prolong the lifespan of orthotopic glioma-bearing rats while maintaining reasonable systemic radiation safety. Therefore, (188)Re-liposome could be a potential therapeutic agent for glioblastoma multiforme treatment.
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Affiliation(s)
- Feng-Yun J Huang
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan
| | - Te-Wei Lee
- Institute of Nuclear Energy Research, Longtan, Taiwan
| | | | | | - Wei-Hsin Hsu
- Institute of Nuclear Energy Research, Longtan, Taiwan
| | - Chien-Wen Chang
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan
| | - Jem-Mau Lo
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan
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Ibrahim T, McLaurin J. Protein seeding in Alzheimer’s disease and Parkinson’s disease: Similarities and differences. World J Neurol 2014; 4:23-35. [DOI: 10.5316/wjn.v4.i4.23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Revised: 11/21/2014] [Accepted: 12/10/2014] [Indexed: 02/06/2023] Open
Abstract
Neurodegenerative pathology can be seeded by introduction of misfolded proteins and peptides into the nervous system. Models of Alzheimer’s disease (AD) and Parkinson’s disease (PD) have both demonstrated susceptibility to this seeding mechanism, emphasizing the role of misfolded conformations of disease-specific proteins and peptides in disease progression. Thinking of the amyloidogenic amyloid-beta peptide (Aβ) and alpha-synuclein (α-syn), of AD and PD, respectively, as prionoids requires a comparison of these molecules and the mechanisms underlying the progression of disease. Aβ and α-syn, despite their size differences, are both natively unstructured and misfold into β-structured conformers. Additionally, several studies implicate the significant role of membrane interactions, such as those with lipid rafts in the plasma membrane, in mediating protein aggregation and transfer of Aβ and α-syn between cells that may be common to both AD and PD. Examination of inter-neuronal transfer of proteins/peptides provides evidence into the core mechanism of neuropathological propagation. Specifically, uptake of aggregates likely occurs by the endocytic pathway, possibly in response to their formation of membrane pores via a mechanism shared with pore-forming toxins. Failure of cellular clearance machinery to degrade misfolded proteins favours their release into the extracellular space, where they can be taken up by directly connected, nearby neurons. Although similarities between AD and PD are frequent and include mechanistically similar transfer processes, what differentiates these diseases, in terms of temporal and spatial patterns of propagation, may be in part due to the differing kinetics of protein misfolding. Several examples of animal models demonstrating seeding and propagation by exogenous treatment with Aβ and α-syn highlight the importance of both the environment in which these seeds are formed as well as the environment into which the seeds are propagated. Although these studies suggest potent seeding effects by both Aβ and α-syn, they emphasize the need for future studies to thoroughly characterize “seeds” as well as analyze changes in the nervous system in response to exogenous insults.
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van de Haar HJ, Burgmans S, Hofman PAM, Verhey FRJ, Jansen JFA, Backes WH. Blood-brain barrier impairment in dementia: current and future in vivo assessments. Neurosci Biobehav Rev 2014; 49:71-81. [PMID: 25524876 DOI: 10.1016/j.neubiorev.2014.11.022] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Revised: 10/20/2014] [Accepted: 11/21/2014] [Indexed: 01/14/2023]
Abstract
Increasing evidence indicates that blood-brain barrier (BBB) impairment may play a role in the pathophysiology of cognitive decline and dementia. In vivo imaging studies are needed to quantify and localize the BBB defects during life, contemplating the circulatory properties. We reviewed the literature for imaging studies investigating BBB impairment in patients suffering from dementia. After selection, 11 imaging studies were included, of which 6 used contrast-enhanced magnetic resonance imaging (MRI), 2 used contrast-enhanced computed tomography (CT), and 3 positron emission tomography (PET). Primarily the MRI studies hint at a subtle increasing permeability of the BBB, particularly in patients already exhibiting cerebrovascular pathology. More elaborate studies are required to provide convincing evidence on BBB impairment in patients with various stages of dementia with and without obvious cerebrovascular pathology. In the future, dynamic contrast enhanced MRI techniques and transport specific imaging using PET may further detail the research on the molecular nature of BBB defects.
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Affiliation(s)
- Harm J van de Haar
- School for Mental Health and Neuroscience, Maastricht University, Dr. Tanslaan 12, 6229 ET, Maastricht, The Netherlands; Department of Psychiatry and Neuropsychology, Alzheimer Center Limburg, Maastricht University Medical Center, Dr. Tanslaan 12, 6229 ET Maastricht, The Netherlands; Departments of Radiology and Nuclear Medicine, Maastricht University Medical Center, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands
| | - Saartje Burgmans
- School for Mental Health and Neuroscience, Maastricht University, Dr. Tanslaan 12, 6229 ET, Maastricht, The Netherlands; Department of Psychiatry and Neuropsychology, Alzheimer Center Limburg, Maastricht University Medical Center, Dr. Tanslaan 12, 6229 ET Maastricht, The Netherlands
| | - Paul A M Hofman
- School for Mental Health and Neuroscience, Maastricht University, Dr. Tanslaan 12, 6229 ET, Maastricht, The Netherlands; Departments of Radiology and Nuclear Medicine, Maastricht University Medical Center, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands
| | - Frans R J Verhey
- School for Mental Health and Neuroscience, Maastricht University, Dr. Tanslaan 12, 6229 ET, Maastricht, The Netherlands; Department of Psychiatry and Neuropsychology, Alzheimer Center Limburg, Maastricht University Medical Center, Dr. Tanslaan 12, 6229 ET Maastricht, The Netherlands
| | - Jacobus F A Jansen
- School for Mental Health and Neuroscience, Maastricht University, Dr. Tanslaan 12, 6229 ET, Maastricht, The Netherlands; Departments of Radiology and Nuclear Medicine, Maastricht University Medical Center, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands
| | - Walter H Backes
- School for Mental Health and Neuroscience, Maastricht University, Dr. Tanslaan 12, 6229 ET, Maastricht, The Netherlands; Departments of Radiology and Nuclear Medicine, Maastricht University Medical Center, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands; CARIM School for Cardiovascular Disease, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.
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Mathieu D, Lecomte R, Tsanaclis AM, Larouche A, Fortin D. Standardization and Detailed Characterization of the Syngeneic Fischer/F98 Glioma Model. Can J Neurol Sci 2014; 34:296-306. [PMID: 17803026 DOI: 10.1017/s0317167100006715] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Introduction:Adequate animal glioma models are mandatory for the pursuit of preclinical research in neuro-oncology. Many implantation models have been described, but none perfectly emulate human malignant gliomas. This work reports our experience in standardizing, optimizing and characterizing the Fischer/F98 glioma model on the clinical, pathological, radiological and metabolic aspects.Materials and methods:F98 cells were implanted in 70 Fischer rats, varying the quantity of cells and volume of implantation solution, and using a micro-infusion pump to minimize implantation trauma, after adequate coordinates were established. Pathological analysis consisted in hematoxylin and eosin (H&E) staining and immunohistochemistry for GFAP, vimentin, albumin, TGF-b1, TGF-b2, CD3 and CD45. Twelve animals were used for MR imaging at 5, 10, 15 and 20 days. Corresponding MR images were compared with pathological slides. Two animals underwent 18F-FDG and 11C-acetate PET studies for metabolic characterization of the tumors.Results:Implantation with 1x104 cells produced a median survival of 26 days and a tumor take of 100%. Large infiltrative neoplasms with a necrotic core were seen on H&E. Numerous mitosis, peritumoral infiltrative behavior, and neovascular proliferation were also obvious. GFAP and vimentin staining was positive inside the tumor cells. Albumin staining was observed in the extracellular space around the tumors. CD3 staining was negligible. The MR images correlated the pathologic findings. 18F-FDG uptake was strong in the tumors.Conclusion:The standardized model described in this study behaves in a predictable and reproducible fashion, and could be considered for future pre-clinical studies. It adequately mimics the behavior of human malignant astrocytomas.
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Affiliation(s)
- David Mathieu
- Department of Surgery, Division of Neurosurgery and Neuro-oncology, Centre Hospitalier Universitaire de Sherbrooke. Sherbrooke University, Sherbrooke, Quebec, Canada
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Palmiotti CA, Prasad S, Naik P, Abul KMD, Sajja RK, Achyuta AH, Cucullo L. In vitro cerebrovascular modeling in the 21st century: current and prospective technologies. Pharm Res 2014; 31:3229-50. [PMID: 25098812 PMCID: PMC4225221 DOI: 10.1007/s11095-014-1464-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Accepted: 07/24/2014] [Indexed: 12/26/2022]
Abstract
The blood-brain barrier (BBB) maintains the brain homeostasis and dynamically responds to events associated with systemic and/or rheological impairments (e.g., inflammation, ischemia) including the exposure to harmful xenobiotics. Thus, understanding the BBB physiology is crucial for the resolution of major central nervous system CNS) disorders challenging both health care providers and the pharmaceutical industry. These challenges include drug delivery to the brain, neurological disorders, toxicological studies, and biodefense. Studies aimed at advancing our understanding of CNS diseases and promoting the development of more effective therapeutics are primarily performed in laboratory animals. However, there are major hindering factors inherent to in vivo studies such as cost, limited throughput and translational significance to humans. These factors promoted the development of alternative in vitro strategies for studying the physiology and pathophysiology of the BBB in relation to brain disorders as well as screening tools to aid in the development of novel CNS drugs. Herein, we provide a detailed review including pros and cons of current and prospective technologies for modelling the BBB in vitro including ex situ, cell based and computational (in silico) models. A special section is dedicated to microfluidic systems including micro-BBB, BBB-on-a-chip, Neurovascular Unit-on-a-Chip and Synthetic Microvasculature Blood-brain Barrier.
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Affiliation(s)
| | - Shikha Prasad
- Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
| | - Pooja Naik
- Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
| | - Kaisar MD Abul
- Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
| | - Ravi K. Sajja
- Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
| | | | - Luca Cucullo
- Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
- Center for Blood Brain Barrier Research, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
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Drug Access to the Central Nervous System in Alzheimer’s Disease: Preclinical and Clinical Insights. Pharm Res 2014; 32:819-39. [DOI: 10.1007/s11095-014-1522-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2014] [Accepted: 09/12/2014] [Indexed: 12/12/2022]
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Agyare EK, Jaruszewski KM, Curran GL, Rosenberg JT, Grant SC, Lowe VJ, Ramakrishnan S, Paravastu AK, Poduslo JF, Kandimalla KK. Engineering theranostic nanovehicles capable of targeting cerebrovascular amyloid deposits. J Control Release 2014; 185:121-9. [PMID: 24735640 DOI: 10.1016/j.jconrel.2014.04.010] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Revised: 03/21/2014] [Accepted: 04/04/2014] [Indexed: 11/26/2022]
Abstract
Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid beta (Aβ) proteins within the walls of the cerebral vasculature with subsequent aggressive vascular inflammation leading to recurrent hemorrhagic strokes. The objective of the study was to develop theranostic nanovehicles (TNVs) capable of a) targeting cerebrovascular amyloid; b) providing magnetic resonance imaging (MRI) contrast for the early detection of CAA; and c) treating cerebrovascular inflammation resulting from CAA. The TNVs comprised of a polymeric nanocore made from Magnevist (MRI contrast agent) conjugated chitosan. The nanocore was also loaded with cyclophosphamide (CYC), an immunosuppressant shown to reduce the cerebrovascular inflammation in CAA. Putrescine modified F(ab')2 fragment of anti-amyloid antibody, IgG4.1 (pF(ab')24.1) was conjugated to the surface of the nanocore to target cerebrovascular amyloid. The average size of the control chitosan nanoparticles (conjugated with albumin and are devoid of Magnevist, CYC, and pF(ab')24.1) was 164±1.2 nm and that of the TNVs was 239±4.1 nm. The zeta potential values of the CCNs and TNVs were 21.6±1.7 mV and 11.9±0.5 mV, respectively. The leakage of Magnevist from the TNVs was a modest 0.2% over 4 days, and the CYC release from the TNVs followed Higuchi's model that describes sustained drug release from polymeric matrices. The studies conducted in polarized human microvascular endothelial cell monolayers (hCMEC/D3) in vitro as well as in mice in vivo have demonstrated the ability of TNVs to target cerebrovascular amyloid. In addition, the TNVs provided contrast for imaging cerebrovascular amyloid using MRI and single photon emission computed tomography. Moreover, the TNVs were shown to reduce pro-inflammatory cytokine production by the Aβ challenged blood brain barrier (BBB) endothelium more effectively than the cyclophosphamide alone.
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Affiliation(s)
- Edward K Agyare
- Division of Basic Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, 1520 S. MLK BLVD, Tallahassee 32307, USA
| | - Kristen M Jaruszewski
- Department of Pharmaceutics and Brain Barriers Research Center, University of Minnesota, 308 Harvard St. SE, Room 9-149A WDH, Minneapolis 55455, USA; Molecular Neurobiology Laboratory, Departments of Neurology, Neuroscience, and Biochemistry/Molecular Biology, Mayo Clinic College of Medicine, 200 1st Street SW, Rochester 55905, USA
| | - Geoffry L Curran
- Molecular Neurobiology Laboratory, Departments of Neurology, Neuroscience, and Biochemistry/Molecular Biology, Mayo Clinic College of Medicine, 200 1st Street SW, Rochester 55905, USA
| | - Jens T Rosenberg
- The Florida State University and National High Magnetic Field Laboratory, 1800 East Paul Dirac Drive, Tallahassee 32310, USA
| | - Samuel C Grant
- The Florida State University and National High Magnetic Field Laboratory, 1800 East Paul Dirac Drive, Tallahassee 32310, USA; Department of Chemical and Biomedical Engineering, Florida A&M University-Florida State University College of Engineering, 2525 Pottsdamer Street, Tallahassee 32310, USA
| | - Val J Lowe
- Nuclear Medicine, Department of Radiology, Mayo Clinic, 200 1st Street SW, Rochester 55905, USA
| | - Subramanian Ramakrishnan
- Department of Chemical and Biomedical Engineering, Florida A&M University-Florida State University College of Engineering, 2525 Pottsdamer Street, Tallahassee 32310, USA
| | - Anant K Paravastu
- The Florida State University and National High Magnetic Field Laboratory, 1800 East Paul Dirac Drive, Tallahassee 32310, USA; Department of Chemical and Biomedical Engineering, Florida A&M University-Florida State University College of Engineering, 2525 Pottsdamer Street, Tallahassee 32310, USA
| | - Joseph F Poduslo
- Molecular Neurobiology Laboratory, Departments of Neurology, Neuroscience, and Biochemistry/Molecular Biology, Mayo Clinic College of Medicine, 200 1st Street SW, Rochester 55905, USA
| | - Karunya K Kandimalla
- Department of Pharmaceutics and Brain Barriers Research Center, University of Minnesota, 308 Harvard St. SE, Room 9-149A WDH, Minneapolis 55455, USA; Molecular Neurobiology Laboratory, Departments of Neurology, Neuroscience, and Biochemistry/Molecular Biology, Mayo Clinic College of Medicine, 200 1st Street SW, Rochester 55905, USA.
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Do TM, Alata W, Dodacki A, Traversy MT, Chacun H, Pradier L, Scherrmann JM, Farinotti R, Calon F, Bourasset F. Altered cerebral vascular volumes and solute transport at the blood-brain barriers of two transgenic mouse models of Alzheimer's disease. Neuropharmacology 2014; 81:311-7. [PMID: 24631967 DOI: 10.1016/j.neuropharm.2014.02.010] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Revised: 02/11/2014] [Accepted: 02/13/2014] [Indexed: 11/30/2022]
Abstract
We evaluated the integrity and function of the blood-brain barrier in 3xTg-AD mice aged 3-18 months and in APP/PS1 mice aged 8-months to determine the impacts of changes in amyloid and tau proteins on the brain vascular changes. The vascular volume (Vvasc) was sub-normal in 3xTg-AD mice aged from 6 to 18 months, but not in the APP/PS1 mice. The uptakes of [(3)H]-diazepam by the brains of 3xTg-AD, APP/PS1 and their age-matched control mice were similar at all the times studied, suggesting that the simple diffusion of small solutes is unchanged in transgenic animals. The uptake of d-glucose by the brains of 18-month old 3xTg-AD mice, but not by those of 8-month old APP/PS1 mice, was reduced compared to their age-matched controls. Accordingly, the amount of Glut-1 protein was 1.4 times lower in the brain capillaries of 18 month-old 3xTg-AD mice than in those of age-matched control mice. We conclude that the brain vascular volume is reduced early in 3xTg-AD mice, 6 months before the appearance of pathological lesions, and that this reduction persists until they are at least 18 months old. The absence of alterations in the BBB of APP/PS1 mice suggests that hyperphosphorylated tau proteins contribute to the vascular changes that occur in AD.
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Affiliation(s)
- Tuan Minh Do
- Laboratoire de Pharmacie Clinique et pharmacocinétique, EA 4123, Université Paris-Sud 11, Faculté de Pharmacie, Châtenay-Malabry, France
| | - Wael Alata
- Faculty of Pharmacy, Laval University, Quebec, QC, Canada
| | - Agnès Dodacki
- Inserm, U1144, Paris F-75006, France; Université Paris Descartes, UMR-S 1144, Paris F-75006, France; Université Paris Diderot, UMR-S 1144, Paris F-75013, France
| | | | - Hélène Chacun
- CNRS UMR 8612, Université Paris Sud, Faculté de Pharmacie, Châtenay-Malabry, France
| | - Laurent Pradier
- Sanofi-Aventis Therapeutic Strategy Unit Aging, Chilly-Mazarin, France
| | - Jean-Michel Scherrmann
- Inserm, U1144, Paris F-75006, France; Université Paris Descartes, UMR-S 1144, Paris F-75006, France; Université Paris Diderot, UMR-S 1144, Paris F-75013, France
| | - Robert Farinotti
- Laboratoire de Pharmacie Clinique et pharmacocinétique, EA 4123, Université Paris-Sud 11, Faculté de Pharmacie, Châtenay-Malabry, France
| | - Frédéric Calon
- Faculty of Pharmacy, Laval University, Quebec, QC, Canada
| | - Fanchon Bourasset
- Inserm, U1144, Paris F-75006, France; Université Paris Descartes, UMR-S 1144, Paris F-75006, France; Université Paris Diderot, UMR-S 1144, Paris F-75013, France.
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45
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Tobinick E. Perispinal etanercept: a new therapeutic paradigm in neurology. Expert Rev Neurother 2014; 10:985-1002. [DOI: 10.1586/ern.10.52] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Jaruszewski KM, Curran GL, Swaminathan SK, Rosenberg JT, Grant SC, Ramakrishnan S, Lowe VJ, Poduslo JF, Kandimalla KK. Multimodal nanoprobes to target cerebrovascular amyloid in Alzheimer's disease brain. Biomaterials 2013; 35:1967-76. [PMID: 24331706 DOI: 10.1016/j.biomaterials.2013.10.075] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2013] [Accepted: 10/27/2013] [Indexed: 12/12/2022]
Abstract
Cerebral amyloid angiopathy (CAA) results from the accumulation of Aβ proteins primarily within the media and adventitia of small arteries and capillaries of the cortex and leptomeninges. CAA affects a majority of Alzheimer's disease (AD) patients and is associated with a rapid decline in cognitive reserve. Unfortunately, there is no pre-mortem diagnosis available for CAA. Furthermore, treatment options are few and relatively ineffective. To combat this issue, we have designed nanovehicles (nanoparticles-IgG4.1) capable of targeting cerebrovascular amyloid (CVA) and serving as early diagnostic and therapeutic agents. These nanovehicles were loaded with Gadolinium (Gd) based (Magnevist(®)) magnetic resonance imaging contrast agents or single photon emission computed tomography (SPECT) agents, such as (125)I. In addition, the nanovehicles carry either anti-inflammatory and anti-amyloidogenic agents such as curcumin or immunosuppressants such as dexamethasone, which were previously shown to reduce cerebrovascular inflammation. Owing to the anti-amyloid antibody (IgG4.1) grafted on the surface, the nanovehicles are capable of specifically targeting CVA deposits. The nanovehicles effectively marginate from the blood flow to the vascular wall as determined by using quartz crystal microbalance with dissipation monitoring (QCM-D) technology. They demonstrate excellent distribution to the brain vasculature and target CVA, thus providing MRI and SPECT contrast specific to the CVA in the brain. In addition, they also display the potential to carry therapeutic agents to reduce cerebrovascular inflammation associated with CAA, which is believed to trigger hemorrhage in CAA patients.
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Affiliation(s)
- Kristen M Jaruszewski
- Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA; Molecular Neurobiology Laboratory, Department of Neurology, Neuroscience and Biochemistry/Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Department of Pharmaceutics, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
| | - Geoffry L Curran
- Molecular Neurobiology Laboratory, Department of Neurology, Neuroscience and Biochemistry/Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
| | - Suresh K Swaminathan
- Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA
| | - Jens T Rosenberg
- The Florida State University and National High Magnetic Field Laboratory, Tallassee, FL 32310, USA
| | - Samuel C Grant
- The Florida State University and National High Magnetic Field Laboratory, Tallassee, FL 32310, USA; Department of Chemical and Biomedical Engineering, College of Engineering, Florida A&M University-Florida State University, Tallahassee, FL 32310, USA
| | - Subramanian Ramakrishnan
- The Florida State University and National High Magnetic Field Laboratory, Tallassee, FL 32310, USA; Department of Chemical and Biomedical Engineering, College of Engineering, Florida A&M University-Florida State University, Tallahassee, FL 32310, USA
| | - Val J Lowe
- Nuclear Medicine, Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA
| | - Joseph F Poduslo
- Molecular Neurobiology Laboratory, Department of Neurology, Neuroscience and Biochemistry/Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
| | - Karunya K Kandimalla
- Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA; Molecular Neurobiology Laboratory, Department of Neurology, Neuroscience and Biochemistry/Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
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47
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Banks WA, Owen JB, Erickson MA. Insulin in the brain: there and back again. Pharmacol Ther 2012; 136:82-93. [PMID: 22820012 PMCID: PMC4134675 DOI: 10.1016/j.pharmthera.2012.07.006] [Citation(s) in RCA: 419] [Impact Index Per Article: 32.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2012] [Accepted: 07/03/2012] [Indexed: 12/12/2022]
Abstract
Insulin performs unique functions within the CNS. Produced nearly exclusively by the pancreas, insulin crosses the blood-brain barrier (BBB) using a saturable transporter, affecting feeding and cognition through CNS mechanisms largely independent of glucose utilization. Whereas peripheral insulin acts primarily as a metabolic regulatory hormone, CNS insulin has an array of effects on brain that may more closely resemble the actions of the ancestral insulin molecule. Brain endothelial cells (BECs), the cells that form the vascular BBB and contain the transporter that translocates insulin from blood to brain, are themselves regulated by insulin. The insulin transporter is altered by physiological and pathological factors including hyperglycemia and the diabetic state. The latter can lead to BBB disruption. Pericytes, pluripotent cells in intimate contact with the BECs, protect the integrity of the BBB and its ability to transport insulin. Most of insulin's known actions within the CNS are mediated through two canonical pathways, the phosphoinositide-3 kinase (PI3)/Akt and Ras/mitogen activated kinase (MAPK) cascades. Resistance to insulin action within the CNS, sometimes referred to as diabetes mellitus type III, is associated with peripheral insulin resistance, but it is possible that variable hormonal resistance syndromes exist so that resistance at one tissue bed may be independent of that at others. CNS insulin resistance is associated with Alzheimer's disease, depression, and impaired baroreceptor gain in pregnancy. These aspects of CNS insulin action and the control of its entry by the BBB are likely only a small part of the story of insulin within the brain.
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Affiliation(s)
- William A Banks
- Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care Center, Seattle, WA, USA.
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48
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Anti-Aβ-MAb and dually decorated nanoliposomes: Effect of Aβ1-42 peptides on interaction with hCMEC/D3 cells. Eur J Pharm Biopharm 2012; 81:49-56. [DOI: 10.1016/j.ejpb.2012.02.006] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2011] [Revised: 02/09/2012] [Accepted: 02/10/2012] [Indexed: 11/18/2022]
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49
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Muller AP, Fernandez AM, Haas C, Zimmer E, Portela LV, Torres-Aleman I. Reduced brain insulin-like growth factor I function during aging. Mol Cell Neurosci 2012; 49:9-12. [PMID: 21807098 DOI: 10.1016/j.mcn.2011.07.008] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2011] [Revised: 07/05/2011] [Accepted: 07/18/2011] [Indexed: 12/31/2022] Open
Abstract
Peripheral insulin-like growth factor I (IGF-I) function progressively deteriorates with age. However, whereas deterioration of IGF-I function in the aged brain seems probable, it has not been directly addressed yet. Because serum IGF-I can enter into the brain through the cerebrospinal fluid (CSF), we examined this route of entrance in aged mice. To distinguish endogenous murine IGF-I from exogenously applied IGF-I, we used human IGF-I. We found that after intraperitoneous injection, CSF levels of human IGF-I were significantly higher in old mice (2 year-old) as compared to young ones (4-month-old). In spite of this increase capacity to take IGF-I from the circulation, brain and plasma IGF-I levels were reduced in naive old mice. Moreover, IGF-I signaling was deteriorated in the brain of aged animals. Basal as well as IGF-I-induced activation of the brain IGF-I receptor/Akt/GSK3 pathway was markedly reduced even though old mice have higher levels of brain IGF-I receptors. These data suggest that increases in brain IGF-I receptors and in the capacity to take up serum IGF-I result ineffective because IGF-I function is reduced and aged mice are cognitively impaired, a trait dependant on preserved serum IGF-I input to the brain.
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Affiliation(s)
- Alexandre Pastoris Muller
- Departamento de Bioquímica, ICBS, UFRGS. Programa de Pós Graduação em Ciências Biológicas-Bioquímica. Porto Alegre, RS, Brazil
| | | | - Clarissa Haas
- Departamento de Bioquímica, ICBS, UFRGS. Programa de Pós Graduação em Ciências Biológicas-Bioquímica. Porto Alegre, RS, Brazil
| | - Eduardo Zimmer
- Departamento de Bioquímica, ICBS, UFRGS. Programa de Pós Graduação em Ciências Biológicas-Bioquímica. Porto Alegre, RS, Brazil
| | - Luis Valmor Portela
- Departamento de Bioquímica, ICBS, UFRGS. Programa de Pós Graduação em Ciências Biológicas-Bioquímica. Porto Alegre, RS, Brazil
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50
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Naik P, Cucullo L. In vitro blood-brain barrier models: current and perspective technologies. J Pharm Sci 2011; 101:1337-54. [PMID: 22213383 DOI: 10.1002/jps.23022] [Citation(s) in RCA: 181] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2011] [Revised: 11/21/2011] [Accepted: 12/01/2011] [Indexed: 01/22/2023]
Abstract
Even in the 21st century, studies aimed at characterizing the pathological paradigms associated with the development and progression of central nervous system diseases are primarily performed in laboratory animals. However, limited translational significance, high cost, and labor to develop the appropriate model (e.g., transgenic or inbred strains) have favored parallel in vitro approaches. In vitro models are of particular interest for cerebrovascular studies of the blood-brain barrier (BBB), which plays a critical role in maintaining the brain homeostasis and neuronal functions. Because the BBB dynamically responds to many events associated with rheological and systemic impairments (e.g., hypoperfusion), including the exposure of potentially harmful xenobiotics, the development of more sophisticated artificial systems capable of replicating the vascular properties of the brain microcapillaries are becoming a major focus in basic, translational, and pharmaceutical research. In vitro BBB models are valuable and easy to use supporting tools that can precede and complement animal and human studies. In this article, we provide a detailed review and analysis of currently available in vitro BBB models ranging from static culture systems to the most advanced flow-based and three-dimensional coculture apparatus. We also discuss recent and perspective developments in this ever expanding research field.
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Affiliation(s)
- Pooja Naik
- Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, USA
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