|
1
|
Valerio LSA, Carrick FR, Bedoya L, Sreerama S, Sugaya K. Neural Differentiation of Induced Pluripotent Stem Cells for a Xenogeneic Material-Free 3D Neurological Disease Model Neurulation from Pluripotent Cells Using a Human Hydrogel. Curr Issues Mol Biol 2023; 45:4574-4588. [PMID: 37367039 DOI: 10.3390/cimb45060290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/14/2023] [Accepted: 05/23/2023] [Indexed: 06/28/2023] Open
Abstract
Alzheimer's Disease (AD) is characterized by synapse and neuronal loss and the accumulation of neurofibrillary tangles and Amyloid β plaques. Despite significant research efforts to understand the late stages of the disease, its etiology remains largely unknown. This is in part because of the imprecise AD models in current use. In addition, little attention has been paid to neural stem cells (NSC), which are the cells responsible for the development and maintenance of brain tissue during an individual's lifespan. Thus, an in vitro 3D human brain tissue model using induced pluripotent stem (iPS) cell-derived neural cells in human physiological conditions may be an excellent alternative to standard models to investigate AD pathology. Following the differentiation process mimicking development, iPS cells can be turned into NSCs and, ultimately, neural cells. During differentiation, the traditionally used xenogeneic products may alter the cells' physiology and prevent accurate disease pathology modeling. Hence, establishing a xenogeneic material-free cell culture and differentiation protocol is essential. This study investigated the differentiation of iPS cells to neural cells using a novel extracellular matrix derived from human platelet lysates (PL Matrix). We compared the stemness properties and differentiation efficacies of iPS cells in a PL matrix against those in a conventional 3D scaffold made of an oncogenic murine-matrix. Using well-defined conditions without xenogeneic material, we successfully expanded and differentiated iPS cells into NSCs via dual-SMAD inhibition, which regulates the BMP and TGF signaling cascades in a manner closer to human conditions. This in vitro, 3D, xenogeneic-free scaffold will enhance the quality of disease modeling for neurodegenerative disease research, and the knowledge produced could be used in developing more effective translational medicine.
Collapse
Affiliation(s)
- Luis Sebastian Alexis Valerio
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA
- Institute for Scientific Research and Technology Services (INDICASAT), City of Knowledge 0801, Panama
- Department of Biotechnology, Acharya Nagarjuna University, Guntur 522510, India
| | - Frederick Robert Carrick
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA
- MGH Institute of Health Professions, Boston, MA 02129, USA
- Centre for Mental Health Research in Association, University of Cambridge, Cambridge CB2 1TN, UK
- Department of Neurology, Carrick Institute, Cape Canaveral, FL 32920, USA
| | - Lina Bedoya
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA
| | - Sandeep Sreerama
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA
| | - Kiminobu Sugaya
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA
- Institute for Scientific Research and Technology Services (INDICASAT), City of Knowledge 0801, Panama
- Department of Biotechnology, Acharya Nagarjuna University, Guntur 522510, India
| |
Collapse
|
|
2
|
Cheng Q, Ma X, Liu J, Feng X, Liu Y, Wang Y, Ni W, Song M. Pharmacological Inhibition of the Asparaginyl Endopeptidase (AEP) in an Alzheimer's Disease Model Improves the Survival and Efficacy of Transplanted Neural Stem Cells. Int J Mol Sci 2023; 24:ijms24097739. [PMID: 37175445 PMCID: PMC10178525 DOI: 10.3390/ijms24097739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 04/21/2023] [Accepted: 04/21/2023] [Indexed: 05/15/2023] Open
Abstract
Stem-cell-based therapy is very promising for Alzheimer's disease (AD), yet has not become a reality. A critical challenge is the transplantation microenvironment, which impacts the therapeutic effect of stem cells. In AD brains, amyloid-beta (Aβ) peptides and inflammatory cytokines continuously poison the tissue microenvironment, leading to low survival of grafted cells and restricted efficacy. It is necessary to create a growth-supporting microenvironment for transplanted cells. Recent advances in AD studies suggest that the asparaginyl endopeptidase (AEP) is a potential intervention target for modifying pathological changes. We here chose APP/PS1 mice as an AD model and employed pharmacological inhibition of the AEP for one month to improve the brain microenvironment. Thereafter, we transplanted neural stem cells (NSCs) into the hippocampus and maintained therapy for one more month. We found that inhibition of AEPs resulted in a significant decrease of Aβ, TNF-α, IL-6 and IL-1β in their brains. In AD mice receiving NSC transplantation alone, the survival of NSCs was at a low level, while in combination with AEP inhibition pre-treatment the survival rate of engrafted cells was doubled. Within the 2-month treatment period, implantation of NSCs plus pre-inhibition of the AEP significantly enhanced neural plasticity of the hippocampus and rescued cognitive impairment. Neither NSC transplantation alone nor AEP inhibition alone achieved significant efficacy. In conclusion, pharmacological inhibition of the AEP ameliorated brain microenvironment of AD mice, and thus improved the survival and therapeutic efficacy of transplanted stem cells.
Collapse
Affiliation(s)
- Qing Cheng
- Department of Pharmacology and Chemical Biology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China
| | - Xiaoli Ma
- Department of Pharmacology and Chemical Biology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China
| | - Jingjing Liu
- Department of Pharmacology and Chemical Biology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China
| | - Xuemei Feng
- Department of Pharmacology and Chemical Biology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China
| | - Yan Liu
- Department of Pharmacology and Chemical Biology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China
| | - Yanxia Wang
- Department of Pharmacology and Chemical Biology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China
| | - Wenwen Ni
- Department of Pharmacology and Chemical Biology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China
| | - Mingke Song
- Department of Pharmacology and Chemical Biology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China
| |
Collapse
|
|
3
|
Ballard C, Aarsland D, Cummings J, O'Brien J, Mills R, Molinuevo JL, Fladby T, Williams G, Doherty P, Corbett A, Sultana J. Drug repositioning and repurposing for Alzheimer disease. Nat Rev Neurol 2020; 16:661-673. [PMID: 32939050 PMCID: PMC8291993 DOI: 10.1038/s41582-020-0397-4] [Citation(s) in RCA: 118] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/24/2020] [Indexed: 12/12/2022]
Abstract
Drug repositioning and repurposing can enhance traditional drug development efforts and could accelerate the identification of new treatments for individuals with Alzheimer disease (AD) dementia and mild cognitive impairment. Transcriptional profiling offers a new and highly efficient approach to the identification of novel candidates for repositioning and repurposing. In the future, novel AD transcriptional signatures from cells isolated at early stages of disease, or from human neurons or microglia that carry mutations that increase the risk of AD, might be used as probes to identify additional candidate drugs. Phase II trials assessing repurposed agents must consider the best target population for a specific candidate therapy as well as the mechanism of action of the treatment. In this Review, we highlight promising compounds to prioritize for clinical trials in individuals with AD, and discuss the value of Delphi consensus methodology and evidence-based reviews to inform this prioritization process. We also describe emerging work, focusing on the potential value of transcript signatures as a cost-effective approach to the identification of novel candidates for repositioning.
Collapse
Affiliation(s)
- Clive Ballard
- College of Medicine and Health, University of Exeter, Exeter, UK.
| | - Dag Aarsland
- Institute of Psychiatry Psychology and Neuroscience, King's College London, London, UK
- SESAM (Regional Center for Elderly Medicine and Interaction), University Hospital Stavanger, Stavanger, Norway
| | - Jeffrey Cummings
- Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA
| | - John O'Brien
- School of Clinical Medicine, University of Cambridge, Cambridge, UK
| | - Roger Mills
- Institute of Psychiatry Psychology and Neuroscience, King's College London, London, UK
- Vincere Consulting, LLC, San Diego, CA, USA
| | | | - Tormod Fladby
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Gareth Williams
- Institute of Psychiatry Psychology and Neuroscience, King's College London, London, UK
| | - Pat Doherty
- Institute of Psychiatry Psychology and Neuroscience, King's College London, London, UK
| | - Anne Corbett
- College of Medicine and Health, University of Exeter, Exeter, UK
| | - Janet Sultana
- Department of Biomedical and Dental Sciences and Morpho-functional Imaging, University of Messina, Messina, Italy
| |
Collapse
|
|
4
|
Turcato F, Kim P, Barnett A, Jin Y, Scerba M, Casey A, Selman W, Greig NH, Luo Y. Sequential combined Treatment of Pifithrin-α and Posiphen Enhances Neurogenesis and Functional Recovery After Stroke. Cell Transplant 2018; 27:607-621. [PMID: 29871513 PMCID: PMC6041885 DOI: 10.1177/0963689718766328] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Objective: Although cerebral ischemia can activate endogenous reparative processes, such as
proliferation of endogenous neural stem cells (NSCs) in the subventricular zone (SVZ)
and subgranular zone (SGZ), the majority of these new cells die shortly after injury and
do not appropriately differentiate into neurons, or migrate and functionally integrate
into the brain. The purpose of this study was to examine a novel strategy for treatment
of stroke after injury by optimizing the survival of ischemia-induced endogenous NSCs in
the SVZ and SGZ. Methods: Adult SVZ and SGZ NSCs were grown as neurospheres in culture and treated with a p53
inactivator, pifithrin-α (PFT-α), and an amyloid precursor protein (APP)-lowering drug,
posiphen, and effects on neurosphere number, size and neuronal differentiation were
evaluated. This combined sequential treatment approach was then evaluated in mice
challenged with middle cerebral artery occlusion (MCAo). Locomotor behavior and
cognition were evaluated at 4 weeks, and the number of new surviving neurons was
quantified in nestin creERT2-YFP mice. Results: PFT-α and posiphen enhanced the self-renewal, proliferation rate and neuronal
differentiation of adult SVZ and SGZ NSCs in culture. Their sequential combination in
mice challenged with MCAo-induced stroke mitigated locomotor and cognitive impairments
and increased the survival of SVZ and SGZ NSCs cells. PFT-α and the combined
posiphen+PFT-α treatment similarly improved locomotion behavior in stroke challenged
mice. Notably, however, the combined treatment provided significantly more potent
cognitive function enhancement in stroke mice, as compared with PFT-α single
treatment. Interpretation: Delayed combined sequential treatment with an inhibitor of p53 dependent apoptosis
(PFT-α) and APP synthesis (posiphen) proved able to enhance stroke-induced endogenous
neurogenesis and improve the functional recovery in stroke animals. Whereas the combined
sequential treatment provided no further improvement in locomotor function, as compared
with PFT-α alone treatment, suggesting a potential ceiling in the locomotion behavioral
outcome in stroke animals, combined treatment more potently augmented cognitive function
recovery after stroke.
Collapse
Affiliation(s)
- Flavia Turcato
- 1 Department of Neurological Surgery, Case Western Reserve University, Cleveland, USA.,2 Department of Physiology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Paul Kim
- 1 Department of Neurological Surgery, Case Western Reserve University, Cleveland, USA
| | - Austin Barnett
- 1 Department of Neurological Surgery, Case Western Reserve University, Cleveland, USA
| | - Yongming Jin
- 1 Department of Neurological Surgery, Case Western Reserve University, Cleveland, USA
| | - Mike Scerba
- 3 National Institute of Aging, Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, Baltimore, USA
| | - Anthony Casey
- 1 Department of Neurological Surgery, Case Western Reserve University, Cleveland, USA
| | - Warren Selman
- 1 Department of Neurological Surgery, Case Western Reserve University, Cleveland, USA
| | - Nigel H Greig
- 3 National Institute of Aging, Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, Baltimore, USA
| | - Yu Luo
- 1 Department of Neurological Surgery, Case Western Reserve University, Cleveland, USA
| |
Collapse
|
|
5
|
Nam H, Lee KH, Nam DH, Joo KM. Adult human neural stem cell therapeutics: Current developmental status and prospect. World J Stem Cells 2015; 7:126-136. [PMID: 25621112 PMCID: PMC4300923 DOI: 10.4252/wjsc.v7.i1.126] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Revised: 09/01/2014] [Accepted: 10/16/2014] [Indexed: 02/06/2023] Open
Abstract
Over the past two decades, regenerative therapies using stem cell technologies have been developed for various neurological diseases. Although stem cell therapy is an attractive option to reverse neural tissue damage and to recover neurological deficits, it is still under development so as not to show significant treatment effects in clinical settings. In this review, we discuss the scientific and clinical basics of adult neural stem cells (aNSCs), and their current developmental status as cell therapeutics for neurological disease. Compared with other types of stem cells, aNSCs have clinical advantages, such as limited proliferation, inborn differentiation potential into functional neural cells, and no ethical issues. In spite of the merits of aNSCs, difficulties in the isolation from the normal brain, and in the in vitro expansion, have blocked preclinical and clinical study using aNSCs. However, several groups have recently developed novel techniques to isolate and expand aNSCs from normal adult brains, and showed successful applications of aNSCs to neurological diseases. With new technologies for aNSCs and their clinical strengths, previous hurdles in stem cell therapies for neurological diseases could be overcome, to realize clinically efficacious regenerative stem cell therapeutics.
Collapse
|
|
6
|
Xue T, Wei L, Zha DJ, Qiao L, Lu LJ, Chen FQ, Qiu JH. Exposure to acoustic stimuli promotes the development and differentiation of neural stem cells from the cochlear nuclei through the clusterin pathway. Int J Mol Med 2015; 35:637-44. [PMID: 25605314 PMCID: PMC4314421 DOI: 10.3892/ijmm.2015.2075] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2014] [Accepted: 01/14/2015] [Indexed: 01/23/2023] Open
Abstract
Stem cell therapy has attracted widespread attention for a number of diseases. Recently, neural stem cells (NSCs) from the cochlear nuclei have been identified, indicating a potential direction for the treatment of sensorineural hearing loss. Acoustic stimuli play an important role in the development of the auditory system. In this study, we aimed to determine whether acoustic stimuli induce NSC development and differentiation through the upregulation of clusterin (CLU) in NSCs isolated from the cochlear nuclei. To further clarify the underlying mechanisms involved in the development and differentiation of NSCs exposed to acoustic stimuli, we successfully constructed animal models in which was CLU silenced by an intraperitoneal injection of shRNA targeting CLI. As expected, the NSCs from rats treated with LV-CLU shRNA exhibited a lower proliferation ratio when exposed to an augmented acoustic environment (AAE). Furthermore, the inhibition of cell apoptosis induced by exposure to AAE was abrogated after silencing the expression of the CLU gene. During the differentiation of acoustic stimuli-exposed stem cells into neurons, the number of astrocytes was significantly reduced, as evidenced by the expression of the cell markers, microtubule associated protein-2 (MAP-2) and glial fibrillary acidic protein (GFAP), which was markedly inhibited when the CLU gene was silenced. Our results indicate that acoustic stimuli may induce the development and differentiation of NSCs from the cochlear nucleus mainly through the CLU pathway. Our study suggests that CLU may be a novel target for the treatment of sensorineural hearing loss.
Collapse
Affiliation(s)
- Tao Xue
- Department of Otolaryngology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Li Wei
- Department of Obstetrics and Gynecology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Ding-Jun Zha
- Department of Otolaryngology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Li Qiao
- Department of Obstetrics and Gynecology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Lian-Jun Lu
- Department of Otolaryngology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Fu-Quan Chen
- Department of Otolaryngology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Jian-Hua Qiu
- Department of Otolaryngology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| |
Collapse
|
|
7
|
Chen J, Pan H, Chen C, Wu W, Iskandar K, He J, Piermartiri T, Jacobowitz DM, Yu QS, McDonough JH, Greig NH, Marini AM. (-)-Phenserine attenuates soman-induced neuropathology. PLoS One 2014; 9:e99818. [PMID: 24955574 PMCID: PMC4067273 DOI: 10.1371/journal.pone.0099818] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Accepted: 05/15/2014] [Indexed: 11/18/2022] Open
Abstract
Organophosphorus (OP) nerve agents are deadly chemical weapons that pose an alarming threat to military and civilian populations. The irreversible inhibition of the critical cholinergic degradative enzyme acetylcholinesterase (AChE) by OP nerve agents leads to cholinergic crisis. Resulting excessive synaptic acetylcholine levels leads to status epilepticus that, in turn, results in brain damage. Current countermeasures are only modestly effective in protecting against OP-induced brain damage, supporting interest for evaluation of new ones. (-)-Phenserine is a reversible AChE inhibitor possessing neuroprotective and amyloid precursor protein lowering actions that reached Phase III clinical trials for Alzheimer's Disease where it exhibited a wide safety margin. This compound preferentially enters the CNS and has potential to impede soman binding to the active site of AChE to, thereby, serve in a protective capacity. Herein, we demonstrate that (-)-phenserine protects neurons against soman-induced neuronal cell death in rats when administered either as a pretreatment or post-treatment paradigm, improves motoric movement in soman-exposed animals and reduces mortality when given as a pretreatment. Gene expression analysis, undertaken to elucidate mechanism, showed that (-)-phenserine pretreatment increased select neuroprotective genes and reversed a Homer1 expression elevation induced by soman exposure. These studies suggest that (-)-phenserine warrants further evaluation as an OP nerve agent protective strategy.
Collapse
Affiliation(s)
- Jun Chen
- Neurology Department, Uniformed Services University of Health Sciences, Bethesda, Maryland, United States of America
| | - Hongna Pan
- Neurology Department, Uniformed Services University of Health Sciences, Bethesda, Maryland, United States of America
| | - Cynthia Chen
- Neurology Department, Uniformed Services University of Health Sciences, Bethesda, Maryland, United States of America
| | - Wei Wu
- Neurology Department, Uniformed Services University of Health Sciences, Bethesda, Maryland, United States of America
| | - Kevin Iskandar
- Neurology Department, Uniformed Services University of Health Sciences, Bethesda, Maryland, United States of America
| | - Jeffrey He
- Neurology Department, Uniformed Services University of Health Sciences, Bethesda, Maryland, United States of America
| | - Tetsade Piermartiri
- Neurology Department, Uniformed Services University of Health Sciences, Bethesda, Maryland, United States of America
| | - David M. Jacobowitz
- Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America
| | - Qian-Sheng Yu
- Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America
| | - John H. McDonough
- Pharmacology Branch, Research Division, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland, United States of America
| | - Nigel H. Greig
- Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America
| | - Ann M. Marini
- Neurology Department, Uniformed Services University of Health Sciences, Bethesda, Maryland, United States of America
| |
Collapse
|
|
8
|
Fan X, Sun D, Tang X, Cai Y, Yin ZQ, Xu H. Stem-cell challenges in the treatment of Alzheimer's disease: a long way from bench to bedside. Med Res Rev 2014; 34:957-78. [PMID: 24500883 DOI: 10.1002/med.21309] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Alzheimer's disease (AD) is the most prevalent type of dementia, and its neuropathology is characterized by deposition of insoluble β-amyloid peptides, intracellular neurofibrillary tangles, and the loss of diverse neurons. Current pharmacological treatments for AD relieve symptoms without affecting the major pathological characteristics of the disease. Therefore, it is essential to develop new and effective therapies. Stem-cell types include tissue-specific stem cells, such as neural stem cells and mesenchymal stem cells, embryonic stem cells derived from blastocysts, and induced pluripotent stem cells (iPSCs) reprogrammed from somatic cells. Recent preclinical evidence suggests that stem cells can be used to treat or model AD. The mechanisms of stem cell based therapies for AD include stem cell mediated neuroprotection and trophic actions, antiamyloidogenesis, beneficial immune modulation, and the replacement of the lost neurons. iPSCs have been recently used to model AD, investigate sporadic and familial AD pathogenesis, and screen for anti-AD drugs. Although considerable progress has been achieved, a series of challenges must be overcome before stem cell based cell therapies are used clinically for AD patients. This review highlights the recent experimental and preclinical progress of stem-cell therapies for AD, and discusses the translational challenges of their clinical application.
Collapse
Affiliation(s)
- Xiaotang Fan
- Department of Histology and Embryology, Third Military Medical University, Chongqing, 400038, P.R. China
| | | | | | | | | | | |
Collapse
|
|
9
|
Bailey AR, Hou H, Song M, Obregon DF, Portis S, Barger S, Shytle D, Stock S, Mori T, Sanberg PG, Murphy T, Tan J. GFAP expression and social deficits in transgenic mice overexpressing human sAPPα. Glia 2013; 61:1556-69. [PMID: 23840007 PMCID: PMC3729742 DOI: 10.1002/glia.22544] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2012] [Revised: 05/14/2013] [Accepted: 05/17/2013] [Indexed: 01/13/2023]
Abstract
Autistic individuals display impaired social interactions and language, and restricted, stereotyped behaviors. Elevated levels of secreted amyloid precursor protein-alpha (sAPPα), the product of α-secretase cleavage of APP, are found in the plasma of some individuals with autism. The sAPPα protein is neurotrophic and neuroprotective and recently showed a correlation to glial differentiation in human neural stem cells (NSCs) via the IL-6 pathway. Considering evidence of gliosis in postmortem autistic brains, we hypothesized that subsets of patients with autism would exhibit elevations in CNS sAPPα and mice generated to mimic this observation would display markers suggestive of gliosis and autism-like behavior. Elevations in sAPPα levels were observed in brains of autistic patients compared to controls. Transgenic mice engineered to overexpress human sAPPα (TgsAPPα mice) displayed hypoactivity, impaired sociability, increased brain glial fibrillary acidic protein (GFAP) expression, and altered Notch1 and IL-6 levels. NSCs isolated from TgsAPPα mice, and those derived from wild-type mice treated with sAPPα, displayed suppressed β-tubulin III and elevated GFAP expression. These results suggest that elevations in brain sAPPα levels are observed in subsets of individuals with autism and TgsAPPα mice display signs suggestive of gliosis and behavioral impairment.
Collapse
Affiliation(s)
- Antoinette R Bailey
- Department of Psychiatry and Neurosciences, Rashid Laboratory for Developmental Neurobiology, Morsani College of Medicine, University of South Florida, Tampa, Florida 33613, USA
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
10
|
Zhang J, Li L, Peng L, Sun Y, Li J. An efficient weighted graph strategy to identify differentiation associated genes in embryonic stem cells. PLoS One 2013; 8:e62716. [PMID: 23638139 PMCID: PMC3637163 DOI: 10.1371/journal.pone.0062716] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2012] [Accepted: 03/25/2013] [Indexed: 11/18/2022] Open
Abstract
In the past few decades, embryonic stem cells (ESCs) were of great interest as a model system for studying early developmental processes and because of their potential therapeutic applications in regenerative medicine. However, the underlying mechanisms of ESC differentiation remain unclear, which limits our exploration of the therapeutic potential of stem cells. Fortunately, the increasing quantity and diversity of biological datasets can provide us with opportunities to explore the biological secrets. However, taking advantage of diverse biological information to facilitate the advancement of ESC research still remains a challenge. Here, we propose a scalable, efficient and flexible function prediction framework that integrates diverse biological information using a simple weighted strategy, for uncovering the genetic determinants of mouse ESC differentiation. The advantage of this approach is that it can make predictions based on dynamic information fusion, owing to the simple weighted strategy. With this approach, we identified 30 genes that had been reported to be associated with differentiation of stem cells, which we regard to be associated with differentiation or pluripotency in embryonic stem cells. We also predicted 70 genes as candidates for contributing to differentiation, which requires further confirmation. As a whole, our results showed that this strategy could be applied as a useful tool for ESC research.
Collapse
Affiliation(s)
- Jie Zhang
- Department of Prevention, Tongji University School of Medicine, Shanghai, China
- * E-mail: (JZ); (JL)
| | - Li Li
- Key Laboratory of Arrhythmias, Ministry of Education, Tongji University School of Medicine, Shanghai, China
| | - Luying Peng
- Key Laboratory of Arrhythmias, Ministry of Education, Tongji University School of Medicine, Shanghai, China
| | - Yingxian Sun
- Department of Cardiology, The First Hospital of China Medical University, Shenyang, China
| | - Jue Li
- Department of Prevention, Tongji University School of Medicine, Shanghai, China
- * E-mail: (JZ); (JL)
| |
Collapse
|
|
11
|
Abstract
Alzheimer's disease (AD) is a progressive neurological disorder characterized by the aggregation of two proteins, amyloid-β and hyperphosphorylated tau, and by neuronal and synaptic loss. Although some drugs have been shown to slow the progression of the disease, at present no treatment has been developed that can stop or reverse the progression of the pathology. Recently, new therapeutic strategies have been proposed for the treatment of the disease. Among these, the development of stem cells and gene-modified cells is an especially promising therapeutic approach for AD. In this review we highlight the experimental and preclinical studies that have been focused on stem cell-based and gene-modified cell-based uses as potential therapies for AD. The potential clinical applications are also discussed.
Collapse
Affiliation(s)
- Micaela Johanna Glat
- Laboratory of Neuroscience, Sackler Faculty of Medicine, Felsenstein Medical Research Center, Tel Aviv University, Petah-Tikva, Israel
| | | |
Collapse
|
|
12
|
Lilja AM, Luo Y, Yu QS, Röjdner J, Li Y, Marini AM, Marutle A, Nordberg A, Greig NH. Neurotrophic and neuroprotective actions of (-)- and (+)-phenserine, candidate drugs for Alzheimer's disease. PLoS One 2013; 8:e54887. [PMID: 23382994 PMCID: PMC3559887 DOI: 10.1371/journal.pone.0054887] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2012] [Accepted: 12/17/2012] [Indexed: 12/11/2022] Open
Abstract
Neuronal dysfunction and demise together with a reduction in neurogenesis are cardinal features of Alzheimer’s disease (AD) induced by a combination of oxidative stress, toxic amyloid-β peptide (Aβ) and a loss of trophic factor support. Amelioration of these was assessed with the Aβ lowering AD experimental drugs (+)-phenserine and (−)-phenserine in neuronal cultures, and actions in mice were evaluated with (+)-phenserine. Both experimental drugs together with the metabolite N1-norphenserine induced neurotrophic actions in human SH-SY5Y cells that were mediated by the protein kinase C (PKC) and extracellular signal–regulated kinases (ERK) pathways, were evident in cells expressing amyloid precursor protein Swedish mutation (APPSWE), and retained in the presence of Aβ and oxidative stress challenge. (+)-Phenserine, together with its (−) enantiomer as well as its N1- and N8-norphenserine and N1,N8-bisnorphenserine metabolites, likewise provided neuroprotective activity against oxidative stress and glutamate toxicity via the PKC and ERK pathways. These neurotrophic and neuroprotective actions were evident in primary cultures of subventricular zone (SVZ) neural progenitor cells, whose neurosphere size and survival were augmented by (+)-phenserine. Translation of these effects in vivo was assessed in wild type and AD APPswe transgenic (Tg2576) mice by doublecortin (DCX) immunohistochemical analysis of neurogenesis in the SVZ, which was significantly elevated by 16 day systemic (+)-phenserine treatment, in the presence of a (+)-phenserine-induced elevation in brain- derived neurotrophic factor (BDNF).
Collapse
Affiliation(s)
- Anna M. Lilja
- Alzheimer Neurobiology Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
- Drug Design and Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America
- * E-mail: (AL); (NHG)
| | - Yu Luo
- Department of Neurological Surgery, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
| | - Qian-sheng Yu
- Drug Design and Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America
| | - Jennie Röjdner
- Alzheimer Neurobiology Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
- Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Yazhou Li
- Drug Design and Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America
| | - Ann M. Marini
- Department of Neurology and Neuroscience Program, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America
| | - Amelia Marutle
- Alzheimer Neurobiology Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Agneta Nordberg
- Alzheimer Neurobiology Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
- Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Nigel H. Greig
- Drug Design and Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America
- * E-mail: (AL); (NHG)
| |
Collapse
|
|
13
|
Mimeault M, Batra SK. Great promise of tissue-resident adult stem/progenitor cells in transplantation and cancer therapies. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2012; 741:171-86. [PMID: 22457110 DOI: 10.1007/978-1-4614-2098-9_12] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Recent progress in tissue-resident adult stem/progenitor cell research has inspired great interest because these immature cells from your own body can act as potential, easily accessible cell sources for cell transplantation in regenerative medicine and cancer therapies. The use of adult stem/progenitor cells endowed with a high self-renewal ability and multilineage differentiation potential, which are able to regenerate all the mature cells in the tissues from their origin, offers great promise in replacing non-functioning or lost cells and regenerating diseased and damaged tissues. The presence of a small subpopulation of adult stem/progenitor cells in most tissues and organs provides the possibility of stimulating their in vivo differentiation, or of using their ex vivo expanded progenies for cell-replacement and gene therapies with multiple applications in humans without a high-risk of graft rejection and major side effects. Among the diseases that could be treated by adult stem cell-based therapies are hematopoietic and immune disorders, multiple degenerative disorders such as Parkinson's and Alzheimer's diseases, Types 1 and 2 diabetes mellitus as well as skin, eye, liver, lung, tooth and cardiovascular disorders. In addition, a combination of the current cancer treatments with an adjuvant treatment consisting of an autologous or allogeneic adult stem/progenitor cell transplantation also represents a promising strategy for treating and even curing diverse aggressive, metastatic, recurrent and lethal cancers. In this chapter, we reviewed the most recent advancements on the characterization of phenotypic and functional properties of adult stem/progenitor cell types found in bone marrow, heart, brain and other tissues and discussed their therapeutic implications in the stem cell-based transplantation therapy.
Collapse
Affiliation(s)
- Murielle Mimeault
- Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA.
| | | |
Collapse
|
|
14
|
Chen FM, Zhao YM, Jin Y, Shi S. Prospects for translational regenerative medicine. Biotechnol Adv 2011; 30:658-72. [PMID: 22138411 DOI: 10.1016/j.biotechadv.2011.11.005] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2011] [Revised: 11/12/2011] [Accepted: 11/15/2011] [Indexed: 02/06/2023]
Abstract
Translational medicine is an evolutional concept that encompasses the rapid translation of basic research for use in clinical disease diagnosis, prevention and treatment. It follows the idea "from bench to bedside and back", and hence relies on cooperation between laboratory research and clinical care. In the past decade, translational medicine has received unprecedented attention from scientists and clinicians and its fundamental principles have penetrated throughout biomedicine, offering a sign post that guides modern medical research toward a patient-centered focus. Translational regenerative medicine is still in its infancy, and significant basic research investment has not yet achieved satisfactory clinical outcomes for patients. In particular, there are many challenges associated with the use of cell- and tissue-based products for clinical therapies. This review summarizes the transformation and global progress in translational medicine over the past decade. The current obstacles and opportunities in translational regenerative medicine are outlined in the context of stem cell therapy and tissue engineering for the safe and effective regeneration of functional tissue. This review highlights the requirement for multi-disciplinary and inter-disciplinary cooperation to ensure the development of the best possible regenerative therapies within the shortest timeframe possible for the greatest patient benefit.
Collapse
Affiliation(s)
- Fa-Ming Chen
- Department of Periodontology & Oral Medicine, School of Stomatology, Fourth Military Medical University, Xi'an 710032, Shaanxi, PR China.
| | | | | | | |
Collapse
|
|
15
|
Diabetes as a risk factor for Alzheimer's disease: insulin signalling impairment in the brain as an alternative model of Alzheimer's disease. Biochem Soc Trans 2011; 39:891-7. [PMID: 21787319 DOI: 10.1042/bst0390891] [Citation(s) in RCA: 108] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Surprisingly little is known about the mechanisms that trigger the onset of AD (Alzheimer's disease) in sporadic forms. A number of risk factors have been identified that may shed light on the mechanisms that may trigger or facilitate the development of AD. Recently, T2DM (Type 2 diabetes mellitus) has been identified as a risk factor for AD. A common observation for both conditions is the desensitization of insulin receptors in the brain. Insulin acts as a growth factor in the brain and is neuroprotective, activates dendritic sprouting, regeneration and stem cell proliferation. The impairment of this important growth factor signal may facilitate the development of AD. Insulin as well as other growth factors have shown neuroprotective properties in preclinical and clinical trials. Several drugs have been developed to treat T2DM, which re-sensitize insulin receptors and may be of use to prevent neurodegenerative processes in the brain. In particular, the incretins GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insolinotropic polypeptide) are hormones that re-sensitize insulin signalling. Incretins also have similar growth-factor-like properties as insulin and are neuroprotective. In mouse models of AD, GLP-1 receptor agonists reduce amyloid plaque formation, reduce the inflammation response in the brain, protect neurons from oxidative stress, induce neurite outgrowth, and protect synaptic plasticity and memory formation from the detrimental effects caused by β-amyloid production and inflammation. Other growth factors such as BDNF (brain-derived neurotrophic factor), NGF (nerve growth factor) or IGF-1 (insulin-like growth factor 1) also have shown a range of neuroprotective properties in preclinical studies. These results show that these growth factors activate similar cell signalling mechanisms that are protective and regenerative, and suggest that the initial process that may trigger the cascade of neurodegenerative events in AD could be the impairment of growth factor signalling such as early insulin receptor desensitization.
Collapse
|
|
16
|
Archer T, Kostrzewa RM, Beninger RJ, Palomo T. Staging neurodegenerative disorders: structural, regional, biomarker, and functional progressions. Neurotox Res 2011; 19:211-34. [PMID: 20393891 DOI: 10.1007/s12640-010-9190-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2010] [Revised: 03/02/2010] [Accepted: 03/30/2010] [Indexed: 12/11/2022]
Abstract
The notion of staging in the neurodegenerative disorders is modulated by the constant and progressive loss of several aspects of brain structural integrity, circuitry, and neuronal processes. These destructive processes eventually remove individuals' abilities to perform at sufficient and necessary functional capacity at several levels of disease severity. The classification of (a) patients on the basis of diagnosis, risk prognosis, and intervention outcome, forms the basis of clinical staging, and (b) laboratory animals on the basis of animal model of brain disorder, extent of insult, and dysfunctional expression, provides the components for the clinical staging and preclinical staging, respectively, expressing associated epidemiological, biological, and genetic characteristics. The major focus of clinical staging in the present account stems from the fundamental notions of Braak staging as they describe the course and eventual prognosis for Alzheimer's disease, Lewy Body dementia, and Parkinson's disease. Mild cognitive impairment, which expresses the decline in episodic and semantic memory performance below the age-adjusted normal range without marked loss of global cognition or activities of daily living, and the applications of longitudinal magnetic resonance imaging, major instruments for the monitoring of either disease progression in dementia, present important challenges for staging concepts. Although Braak notions present the essential basis for further developments, current staging conceptualizations seem inadequate to comply with the massive influx of information dealing with neurodegenerative processes in brain, advanced both under clinical realities, and discoveries in the laboratory setting. The contributions of various biomarkers of disease progression, e.g., amyloid precursor protein, and neurotransmitter system imbalances, e.g., dopamine receptor supersensitivity and interactive propensities, await their incorporation into the existing staging models thereby underlining the ongoing, dynamic feature of the staging of brain disorders.
Collapse
Affiliation(s)
- Trevor Archer
- Department of Psychology, University of Gothenburg, Box 500, SE-405 30 Gothenburg, Sweden.
| | | | | | | |
Collapse
|
|
17
|
Dantuma E, Merchant S, Sugaya K. Stem cells for the treatment of neurodegenerative diseases. Stem Cell Res Ther 2010; 1:37. [PMID: 21144012 PMCID: PMC3025439 DOI: 10.1186/scrt37] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Stem cells offer an enormous pool of resources for the understanding of the human body. One proposed use of stem cells has been as an autologous therapy. The use of stem cells for neurodegenerative diseases has become of interest. Clinical applications of stem cells for Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis will increase in the coming years, and although great care will need to be taken when moving forward with prospective treatments, the application of stem cells is highly promising.
Collapse
Affiliation(s)
- Elise Dantuma
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 6900 Lake Nona Boulevard, Orlando, FL 32827, USA.
| | | | | |
Collapse
|
|
18
|
Fleisch VC, Fraser B, Allison WT. Investigating regeneration and functional integration of CNS neurons: lessons from zebrafish genetics and other fish species. Biochim Biophys Acta Mol Basis Dis 2010; 1812:364-80. [PMID: 21044883 DOI: 10.1016/j.bbadis.2010.10.012] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2010] [Revised: 10/05/2010] [Accepted: 10/21/2010] [Indexed: 12/21/2022]
Abstract
Zebrafish possess a robust, innate CNS regenerative ability. Combined with their genetic tractability and vertebrate CNS architecture, this ability makes zebrafish an attractive model to gain requisite knowledge for clinical CNS regeneration. In treatment of neurological disorders, one can envisage replacing lost neurons through stem cell therapy or through activation of latent stem cells in the CNS. Here we review the evidence that radial glia are a major source of CNS stem cells in zebrafish and thus activation of radial glia is an attractive therapeutic target. We discuss the regenerative potential and the molecular mechanisms thereof, in the zebrafish spinal cord, retina, optic nerve and higher brain centres. We evaluate various cell ablation paradigms developed to induce regeneration, with particular emphasis on the need for (high throughput) indicators that neuronal regeneration has restored sensory or motor function. We also examine the potential confound that regeneration imposes as the community develops zebrafish models of neurodegeneration. We conclude that zebrafish combine several characters that make them a potent resource for testing hypotheses and discovering therapeutic targets in functional CNS regeneration. This article is part of a Special Issue entitled Zebrafish Models of Neurological Diseases.
Collapse
Affiliation(s)
- Valerie C Fleisch
- Centre for Prions & Protein Folding Disease, University of Alberta, Edmonton, Alberta, Canada.
| | | | | |
Collapse
|
|
19
|
Abstract
Neurodegenerative diseases are characterized by neurodegenerative changes or apoptosis of neurons involved in networks, leading to permanent paralysis and loss of sensation below the site of the injury. Cell replacement therapy has provided the basis for the development of potentially powerful new therapeutic strategies for a broad spectrum of human neurological diseases. In recent years, neurons and glial cells have successfully been generated from stem cells, and extensive efforts by investigators to develop stem cell-based brain transplantation therapies have been carried out. We review here notable previously published experimental and preclinical studies involving stem cell-based cell for neurodegenerative diseases and discuss the future prospects for stem cell therapy of neurological disorders in the clinical setting. Steady and solid progress in stem cell research in both basic and preclinical settings should support the hope for development of stem cell-based cell therapies for neurological diseases.
Collapse
Affiliation(s)
| | | | | | - Ning Zhang
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +86 57186021763; Fax: +86 57187022776
| |
Collapse
|
|
20
|
Yu H, Cao B, Feng M, Zhou Q, Sun X, Wu S, Jin S, Liu H, Lianhong J. Combinated transplantation of neural stem cells and collagen type I promote functional recovery after cerebral ischemia in rats. Anat Rec (Hoboken) 2010; 293:911-7. [PMID: 20191618 DOI: 10.1002/ar.20941] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Using tissue engineering, a complex of neural stem cells (NSCs) and collagen type I was transplanted for the therapy of cerebral ischemic injury. NSCs from E14 d rats were dissociated and cultured by neurosphere formation in serum-free medium in the presence of basic fibroblast growth factor (bFGF), then seeded onto collagen to measure cell adhesive ability. BrdU was added to the culture medium to label the NSCs. Wistar rats (n=100) were subjected to 2-hour middle cerebral artery occlusion. After 24 hours of reperfusion, rats were assigned randomly to five groups: NSCs-collagen repair group, NSCs repair group, unseeded collagen repair group, MCAO medium group, and sham group. Neurological, immunohistological and electronic microscope assessments were performed to examine the effects of these treatments. Scanning electronic microscopy showed that NSCs assemble in the pores of collagen. At 3, 7, 15, and 30 d after transplantation of the NSC-collagen complex, some of the engrafted NSCs survive, differentiate and form synapses in the brains of rats subjected to cerebral ischemia. Six d after transplantation of the NSC-collagen complex into the brains of ischemic rats, the collagen began to degrade; 30 d after transplantation, the collagen had degraded completely. The implantation of NSCs and type I collagen facilitated the structural and functional recovery of neural tissue following ischemic injury.
Collapse
Affiliation(s)
- Hongwei Yu
- Department of Histology and Embryology, Harbin Medical University, Harbin, China
| | | | | | | | | | | | | | | | | |
Collapse
|
|
21
|
Abstract
Type 2 diabetes has been identified as a risk factor for Alzheimer's disease (AD). The underlying mechanism behind this unexpected link is most likely linked to the observed desensitization of insulin receptors in the brain. Insulin acts as a growth factor in the brain and supports neuronal repair, dendritic sprouting, and differentiation. Several drugs have been developed to treat type 2 diabetes which re-synthesize insulin receptors and may be of use to prevent neurodegenerative developments in AD. The incretin glucagon-like peptide-1 (GLP-1) is a hormone that facilitates insulin release under high blood sugar conditions. Interestingly, GLP-1 also has very similar growth factor like properties as insulin, and has been shown to protect neurons from toxic effects. In preclinical studies, GLP-1 and longer lasting analogues reduce apoptosis, protect neurons from oxidative stress, induce neurite outgrowth, protect synaptic plasticity and memory formation from the detrimental effects of β-amyloid, and reduce plaque formation and the inflammation response in the brains of mouse models of AD. An advantage of GLP-1 is that it does not affect blood sugar levels in nondiabetic people. Furthermore, recent research has shown that some GLP-1 analogues can cross the blood-brain barrier, including two that are on the market as a treatment for type 2 diabetes. Therefore, GLP-1 analogues show great promise as a novel treatment for AD or other neurodegenerative conditions.
Collapse
|
|
22
|
Ukrainets IV, Tkach AA, Grinevich LA, Turov AV, Bevz OV. 4-Hydroxy-2-quinolones. 154*. Pyrimidin- 2-ylamides of 1-r-4-hydroxy-2-oxo-1,2-dihydro- quinoline-3-carboxylic acids. synthesis, structure, and properties. Chem Heterocycl Compd (N Y) 2009. [DOI: 10.1007/s10593-009-0297-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
|
|
23
|
Nikolic B, Faintuch S, Goldberg SN, Kuo MD, Cardella JF. Stem Cell Therapy: A Primer for Interventionalists and Imagers. J Vasc Interv Radiol 2009; 20:999-1012. [DOI: 10.1016/j.jvir.2009.04.075] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2009] [Revised: 04/24/2009] [Accepted: 04/28/2009] [Indexed: 02/06/2023] Open
|
|
24
|
Robles A. Pharmacological Treatment of Alzheimer's Disease: Is it Progressing Adequately? Open Neurol J 2009; 3:27-44. [PMID: 19461897 PMCID: PMC2684708 DOI: 10.2174/1874205x00903010027] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2008] [Revised: 12/26/2008] [Accepted: 01/02/2009] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION Between 1993 and 2000 four acetylcholinesterase inhibitors were marketed as a symptomatic treatment for Alzheimer's disease (AD), as well as memantine in 2003. Current research is focused on finding drugs that favorably modify the course of the disease. However, their entrance into the market does not seem to be imminent. RESEARCH DEVELOPMENT The aim of AD research is to find substances that inhibit certain elements of the AD pathogenic chain (beta- and gamma-secretase inhibitors, alpha-secretase stimulants, beta-amyloid aggregability reducers or disaggregation and elimination inductors, as well as tau-hyperphosphorylation, glutamate excitotoxicity, oxidative stress and mitochondrial damage reducers, among other action mechanisms). Demonstrating a disease's retarding effect demands longer trials than those necessary to ascertain symptomatic improvement. Besides, a high number of patients (thousands of them) is necessary, all of which turns out to be difficult and costly. Furthermore, it would be necessary to count on diagnosis and progression markers in the disease's pre-clinical stage, markers for specific phenotypes, as well as high-selectivity molecules acting only where necessary. In order to compensate these difficulties, drugs acting on several defects of the pathogenic chain or showing both symptomatic and neuroprotective action simultaneously are being researched. CONCLUSIONS There are multiple molecules used in research to modify AD progression. Although it turns out to be difficult to obtain drugs with sufficient efficacy so that their marketing is approved, if they were achieved they would lead to a reduction of AD prevalence.
Collapse
Affiliation(s)
- Alfredo Robles
- La Rosaleda Hospital, Santiago León de Caracas street, no. 1, 15706 – Santiago de Compostela, Spain
| |
Collapse
|
|
25
|
New roles for insulin-like hormones in neuronal signalling and protection: new hopes for novel treatments of Alzheimer's disease? Neurobiol Aging 2008; 31:1495-502. [PMID: 18930564 DOI: 10.1016/j.neurobiolaging.2008.08.023] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2008] [Revised: 06/21/2008] [Accepted: 08/30/2008] [Indexed: 01/06/2023]
Abstract
Type 2 diabetes has been identified as a risk factor for Alzheimer's disease (AD). This is most likely due to the desensitisation of insulin receptors in the brain. Insulin acts as a growth factor and supports neuronal repair, dendritic sprouting, and differentiation. This review discusses the potential role that insulin-like hormones could play in ameliorating the reduced growth factor signalling in the brains of people with AD. The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have very similar properties in protecting neurons from toxic effects, and are capable of reversing the detrimental effects that beta-amyloid fragments have on synaptic plasticity. Therefore, incretins show great promise as a novel treatment for reducing degenerative processes in AD.
Collapse
|
|
26
|
Mason C, Dunnill P. The strong financial case for regenerative medicine and the regen industry. Regen Med 2008; 3:351-63. [PMID: 18462058 DOI: 10.2217/17460751.3.3.351] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Although the therapeutic promise of regenerative medicine is immensely exciting, the cost of product development, and particularly of clinical trials, for the more demanding applications will be high. For this reason it is vital for scientists and start-ups who wish to see their ideas implemented to be able to convince established major pharmaceutical or device companies with the necessary 'deep pockets' that the expenditure can yield an appropriate return. It also means that governments and health insurance companies must see a gain in funding regenerative medicine for patients. To address this issue the costs of five major medical conditions that could benefit from regenerative medicine have been defined for the USA as an illustration. This choice of country was made as potentially the largest initial market and one where the billing system for healthcare allows access to individual direct and some indirect costs. The data are complemented by a number of relevant examples of costs per quality-adjusted life year to indicate where current treatment methods are weak or strong. Finally, the relationship of the nascent regen* industry to the pharma and medical device sectors is summarized to assess the challenge of encouraging their involvement.
Collapse
Affiliation(s)
- Chris Mason
- Advanced Centre for Biochemical Engineering, University College London, London, WCIE 7JE, UK.
| | | |
Collapse
|