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Librizzi L, Verde DV, de Curtis M. Causal correlation between seizure activity and brain damage. Neurol Sci 2025:10.1007/s10072-025-08209-4. [PMID: 40402385 DOI: 10.1007/s10072-025-08209-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 04/21/2025] [Indexed: 05/23/2025]
Abstract
INTRODUCTION The correlation between seizure activity and brain damage represents one of the critical issue in epilepsy. In spite of the extensive literature on the topic, very few studies addressed the causal relation between brain tissue worsening and seizure recurrence. We specifically address this issue in the present manuscript. We define potential scenarios and review evidence of causality between seizures recurrence and brain injury in focal structural epilepsies, such as temporal lobe epilepsy and focal cortical dysplasia and extend the analysis to the pathophysiology of the aging brain. RESULTS Experimental findings based on temporal lobe epilepsy models suggest that only conditions characterized by convulsive status epilepticus can induce secondary epileptogenesis that add injury to the brain tissue. When addressing late-onset epilepsies in elderly, it is still not clear whether seizures exacerbate the progression of the underlying pathological brain condition. CONCLUSION At the light of these results, we cannot conclude that seizures as such are responsible for a direct alteration of the brain tissue, whereas experimental evidence suggests that severe convulsive seizures may worsen an ongoing pathological process.
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Affiliation(s)
- Laura Librizzi
- Epilepsy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Diogo Vila Verde
- Epilepsy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Marco de Curtis
- Epilepsy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
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2
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Joshi A, Lehene S, Mishra A. Non-transgenic rodent models of Alzheimer's disease for preclinical research: a review. Mol Biol Rep 2025; 52:456. [PMID: 40366433 DOI: 10.1007/s11033-025-10549-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Accepted: 04/25/2025] [Indexed: 05/15/2025]
Abstract
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by progressive memory loss and cognitive decline. It involves the irreversible destruction of higher brain structures, leading to significant cognitive deficits, personality changes, and aberrant behavior. Key pathological features include the accumulation of amyloid-beta (Aβ) plaques and hyperphosphorylated tau protein neurofibrillary tangles, which disrupt cellular communication and neuron function. Chronic inflammation, vascular abnormalities, and genetic factors like the APOE (apolipoprotein E) ε4 allele also play crucial roles in AD progression. Epidemiological data indicate a substantial global impact, especially among older adults, with women disproportionately affected. Animal models, both transgenic and non-transgenic, are pivotal in researching AD pathophysiology and potential treatments. This review presents a full overview regarding a variety of non-transgenic rodent models of Alzheimer's disease utilized in the preclinical research for treatment approaches in Alzheimer's disease.
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Affiliation(s)
- Abhishek Joshi
- Department of Pharmacology, Dr. Chunibhai Vallabbhai Patel College of Pharmacy, Uka Tarsadia University, Maliba Campus, Bardoli, Gujarat, India.
| | | | - Ashish Mishra
- Department of Pharmaceutics, Dr. Chunibhai Vallabbhai Patel College of Pharmacy, Uka Tarsadia University, Maliba Campus, Bardoli, Gujarat, India
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Lino-Alvarado A, Maia OAC, Oliveira MA, Takakura AC, Tavares-Lima W, Moriya HT, Moreira TS. Central and peripheral mechanisms underlying respiratory deficits in a mouse model of accelerated senescence. Pflugers Arch 2024; 476:1665-1676. [PMID: 39150501 DOI: 10.1007/s00424-024-03006-y] [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: 04/12/2024] [Revised: 07/24/2024] [Accepted: 08/06/2024] [Indexed: 08/17/2024]
Abstract
Aging invariably decreases sensory and motor stimuli and affects several neuronal systems and their connectivity to key brain regions, including those involved in breathing. Nevertheless, further investigation is needed to fully comprehend the link between senescence and respiratory function. Here, we investigate whether a mouse model of accelerated senescence could develop central and peripheral respiratory abnormalities. Adult male Senescence Accelerated Mouse Prone 8 (SAMP8) and the control SAMR1 mice (10 months old) were used. Ventilatory parameters were assessed by whole-body plethysmography, and measurements of respiratory input impedance were performed. SAMP8 mice exhibited a reduction in the density of neurokinin-1 receptor immunoreactivity in the entire ventral respiratory column. Physiological experiments showed that SAMP8 mice exhibited a decreased tachypneic response to hypoxia (FiO2 = 0.08; 10 min) or hypercapnia (FiCO2 = 0.07; 10 min). Additionally, the ventilatory response to hypercapnia increased further due to higher tidal volume. Measurements of respiratory mechanics in SAMP8 mice showed decreased static compliance (Cstat), inspiratory capacity (IC), resistance (Rn), and elastance (H) at different ages (3, 6, and 10 months old). SAMP8 mice also have a decrease in contractile response to methacholine compared to SAMR1. In conclusion, our findings indicate that SAMP8 mice display a loss of the NK1-expressing neurons in the respiratory brainstem centers, along with impairments in both central and peripheral respiratory mechanisms. These observations suggest a potential impact on breathing in a senescence animal model.
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Affiliation(s)
| | - Octavio A C Maia
- Department of Physiology and Biophysics, Institute of Biomedical Science, University of Sao Paulo, Sao Paulo, SP, Brazil
| | - Maria Aparecida Oliveira
- Deptartment of Pharmacology, Institute of Biomedical Science, University of Sao Paulo, Sao Paulo, SP, Brazil
| | - Ana C Takakura
- Deptartment of Pharmacology, Institute of Biomedical Science, University of Sao Paulo, Sao Paulo, SP, Brazil
| | - Wothan Tavares-Lima
- Deptartment of Pharmacology, Institute of Biomedical Science, University of Sao Paulo, Sao Paulo, SP, Brazil
| | - Henrique T Moriya
- Biomedical Engineering Laboratory, University of Sao Paulo, Sao Paulo, SP, Brazil
| | - Thiago S Moreira
- Department of Physiology and Biophysics, Institute of Biomedical Science, University of Sao Paulo, Sao Paulo, SP, Brazil.
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Zheng Y, Yasuda M, Yamao M, Gokan T, Sejima Y, Nishikawa T, Katayama S. Fermented soybean foods (natto) ameliorate age-related cognitive decline by hippocampal TAAR1-mediated activation of the CaMKII/CREB/BDNF signaling pathway in senescence-accelerated mouse prone 8 (SAMP8). Food Funct 2023; 14:10097-10106. [PMID: 37870125 DOI: 10.1039/d3fo03987k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2023]
Abstract
Natto is a traditional fermented soybean-based food that has been an integral part of Japanese cuisine for several centuries. Although there have been extensive studies on the cognitive benefits of soybeans, only limited studies have examined the effects of natto on cognitive function. This study investigated the potential cognitive benefits of natto in senescence-accelerated mouse-prone 8 (SAMP8) mice. After 12 weeks of oral administering natto fermented for 18 h, the spatial learning and memory performance were improved compared with those in SAMP8 control mice. Furthermore, activation of the brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)/cAMP response element-binding protein (CREB) signaling and N-methyl-D-aspartate receptor (NMDAR)-calcium/calmodulin-dependent protein kinase II (CaMKII) cascade was observed in the hippocampus of SAMP8 mice that were fed natto. Additionally, natto administration upregulated trace amine-associated receptor 1 (TAAR1) as a modulator of NMDAR. These findings suggest that natto ameliorates cognitive decline by activating the TAAR1-mediated CaMKII/CREB/BDNF signaling pathway in the hippocampus of SAMP8 mice.
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Affiliation(s)
- Yifeng Zheng
- Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano 399-4598, Japan.
| | - Mayu Yasuda
- Department of Agriculture, Graduate School of Science and Technology, Shinshu University, 8304 Minamiminowa Kamiina, Nagano 399-4598, Japan
| | - Mizuki Yamao
- Department of Agriculture, Graduate School of Science and Technology, Shinshu University, 8304 Minamiminowa Kamiina, Nagano 399-4598, Japan
| | - Toshiya Gokan
- Takano Foods Co., Ltd, 1542 Noda, Omitama, Ibaraki 311-3411, Japan.
| | - Yudai Sejima
- Takano Foods Co., Ltd, 1542 Noda, Omitama, Ibaraki 311-3411, Japan.
| | | | - Shigeru Katayama
- Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano 399-4598, Japan.
- Department of Agriculture, Graduate School of Science and Technology, Shinshu University, 8304 Minamiminowa Kamiina, Nagano 399-4598, Japan
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Polonio AM, Medrano M, Chico-Sordo L, Córdova-Oriz I, Cozzolino M, Montans J, Herraiz S, Seli E, Pellicer A, García-Velasco JA, Varela E. Impaired telomere pathway and fertility in Senescence-Accelerated Mice Prone 8 females with reproductive senescence. Aging (Albany NY) 2023; 15:4600-4624. [PMID: 37338562 DOI: 10.18632/aging.204731] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 05/04/2023] [Indexed: 06/21/2023]
Abstract
Ovarian aging is the main cause of infertility and telomere attrition is common to both aging and fertility disorders. Senescence-Accelerated Mouse Prone 8 (SAMP8) model has shortened lifespan and premature infertility, reflecting signs of reproductive senescence described in middle-aged women. Thus, our objective was to study SAMP8 female fertility and the telomere pathway at the point of reproductive senescence. The lifespan of SAMP8 and control mice was monitored. Telomere length (TL) was measured by in situ hybridization in blood and ovary. Telomerase activity (TA) was analyzed by telomere-repeat amplification protocol, and telomerase expression, by real-time quantitative PCR in ovaries from 7-month-old SAMP8 and controls. Ovarian follicles at different stages of maturation were evaluated by immunohistochemistry. Reproductive outcomes were analyzed after ovarian stimulation. Unpaired t-test or Mann-Whitney test were used to calculate p-values, depending on the variable distribution. Long-rank test was used to compare survival curves and Fisher's exact test was used in contingency tables. Median lifespan of SAMP8 females was reduced compared to SAMP8 males (p = 0.0138) and control females (p < 0.0001). In blood, 7-month-old SAMP8 females presented lower mean TL compared to age-matched controls (p = 0.041). Accordingly, the accumulation of short telomeres was higher in 7-month-old SAMP8 females (p = 0.0202). Ovarian TA was lower in 7-month-old SAMP8 females compared to controls. Similarly, telomerase expression was lower in the ovaries of 7-month-old SAMP8 females (p = 0.04). Globally, mean TL in ovaries and granulosa cells (GCs) were similar. However, the percentage of long telomeres in ovaries (p = 0.004) and GCs (p = 0.004) from 7-month-old SAMP8 females was lower compared to controls. In early-antral and antral follicles, mean TL of SAMP8 GCs was lower than in age-matched controls (p = 0.0156 for early-antral and p = 0.0037 for antral follicles). Middle-aged SAMP8 showed similar numbers of follicles than controls, although recovered oocytes after ovarian stimulation were lower (p = 0.0068). Fertilization rate in oocytes from SAMP8 was not impaired, but SAMP8 mice produced significantly more morphologically abnormal embryos than controls (27.03% in SAMP8 vs. 1.22% in controls; p < 0.001). Our findings suggest telomere dysfunction in SAMP8 females, at the time of reproductive senescence.
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Affiliation(s)
- Alba M Polonio
- IVI Foundation, The Health Research Institute La Fe (IIS La Fe), Valencia, Spain
| | - Marta Medrano
- IVI Foundation, The Health Research Institute La Fe (IIS La Fe), Valencia, Spain
| | - Lucía Chico-Sordo
- IVI Foundation, The Health Research Institute La Fe (IIS La Fe), Valencia, Spain
| | - Isabel Córdova-Oriz
- IVI Foundation, The Health Research Institute La Fe (IIS La Fe), Valencia, Spain
| | | | | | - Sonia Herraiz
- IVI Foundation, The Health Research Institute La Fe (IIS La Fe), Valencia, Spain
| | - Emre Seli
- IVIRMA New Jersey, Basking Ridge, NJ 07920, USA
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Heaven, CT 06510, USA
| | - Antonio Pellicer
- IVIRMA Rome, Rome, Italy
- Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, Valencia, Spain
| | - Juan A García-Velasco
- IVI Foundation, The Health Research Institute La Fe (IIS La Fe), Valencia, Spain
- IVIRMA Madrid, Madrid, Spain
- Department of Obstetrics and Gynecology, Rey Juan Carlos University, Madrid, Spain
| | - Elisa Varela
- IVI Foundation, The Health Research Institute La Fe (IIS La Fe), Valencia, Spain
- Department of Obstetrics and Gynecology, Rey Juan Carlos University, Madrid, Spain
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Kirchner S, Lei V, Kim P, Patel M, Shannon J, Corcoran D, Hughes D, Waters D, Dzirasa K, Erdmann D, Coers J, MacLeod A, Zhang JY. An Aging-Susceptible Circadian Rhythm Controls Cutaneous Antiviral Immunity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.14.536934. [PMID: 37131751 PMCID: PMC10153172 DOI: 10.1101/2023.04.14.536934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
Aged skin is prone to viral infections, but the mechanisms responsible for this immunosenescent immune risk are unclear. We observed that aged murine and human skin expressed reduced antiviral proteins (AVPs) and circadian regulators including Bmal1 and Clock. Bmal1 and Clock were found to control rhythmic AVP expression in skin and such circadian-control of AVPs was diminished by disruption of immune cell interleukin 27 signaling and deletion of Bmal1/Clock genes in mouse skins, as well as siRNA-mediated knockdown of CLOCK in human primary keratinocytes. We found that treatment of circadian enhancing agents, nobiletin and SR8278, reduced infection of herpes simplex virus 1 (HSV1) in epidermal explants and human keratinocytes in a Bmal1/Clock-dependent manner. Circadian enhancing treatment also reversed susceptibility of aging murine skin and human primary keratinocytes to viral infection. These findings reveal an evolutionarily conserved and age-sensitive circadian regulation of cutaneous antiviral immunity, underscoring circadian restoration as an antiviral strategy in aging populations.
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Lyu W, Kousaka M, Jia H, Kato H. Effects of Turmeric Extract on Age-Related Skeletal Muscle Atrophy in Senescence-Accelerated Mice. Life (Basel) 2023; 13:life13040941. [PMID: 37109470 PMCID: PMC10141758 DOI: 10.3390/life13040941] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/14/2023] [Accepted: 03/31/2023] [Indexed: 04/07/2023] Open
Abstract
Muscle atrophy is one of the main causes of sarcopenia—the age-related loss of skeletal muscle. In this study, we investigated the effect of turmeric (Curcuma longa) extract (TE) supplementation on age-related muscle atrophy in a senescence-accelerated mouse model and explored the underlying mechanisms. Twenty-six-week-old male, senescence-accelerated mouse resistant (SAMR) mice received the AIN-93G basal diet, while twenty-six-week-old male, senescence-accelerated mouse prone 8 (SAMP8) mice received the AIN-93G basal diet or a 2% TE powder-supplemented diet for ten weeks. Our findings revealed that TE supplementation showed certain effects on ameliorating the decrease in body weight, tibialis anterior weight, and mesenteric fat tissue weight in SAMP8 mice. TE improved gene expression in the glucocorticoid receptor-FoxO signaling pathway in skeletal muscle, including redd1, klf15, foxo1, murf1, and mafbx. Furthermore, TE might have the certain potential on improving the dynamic balance between anabolic and catabolic processes by inhibiting the binding of glucocorticoid receptor or FoxO1 to the glucocorticoid response element or FoxO-binding element in the MuRF1 promoter in skeletal muscle, thereby promoting muscle mass and strength, and preventing muscle atrophy and sarcopenia prevention. Moreover, TE may have reduced mitochondrial damage and maintained cell growth and division by downregulating the mRNA expression of the genes mfn2 and tsc2. Thus, the results indicated TE’s potential for preventing age-related muscle atrophy and sarcopenia.
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Affiliation(s)
- Weida Lyu
- Health Nutrition, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0032, Japan
- Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0032, Japan
| | - Marika Kousaka
- Health Nutrition, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0032, Japan
| | - Huijuan Jia
- Health Nutrition, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0032, Japan
| | - Hisanori Kato
- Health Nutrition, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0032, Japan
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Ghanam AR, Ke S, Wang S, Elgendy R, Xie C, Wang S, Zhang R, Wei M, Liu W, Cao J, Zhang Y, Zhang Z, Xue T, Zheng Y, Song X. Alternative transcribed 3' isoform of long non-coding RNA Malat1 inhibits mouse retinal oxidative stress. iScience 2023; 26:105740. [PMID: 36594014 PMCID: PMC9804114 DOI: 10.1016/j.isci.2022.105740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 03/08/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022] Open
Abstract
The function of the cancer-associated lncRNA Malat1 during aging is as-of-yet uncharacterized. Here, we show that Malat1 interacts with Nucleophosmin (NPM) in young mouse brain, and with Lamin A/C, hnRNP C, and KAP1 with age. RNA-seq and RT-qPCR reveal a persistent expression of Malat1_2 (the 3'isoform of Malat1) in Malat1Δ1 (5'-1.5 kb deletion) mouse retinas and brains at 1/4th level of the full-length Malat1, while Malat1_1 (the 5'isoform) in Malat1Δ2 (deletion of 3'-conserved 5.7 kb) at a much lower level, suggesting an internal promoter driving the 3' isoform. The 1774 and 496 differentially expressed genes in Malat1Δ2 and Malat1Δ1 brains, respectively, suggest the 3' isoform regulates gene expression in trans and the 5' isoform in cis. Consistently, Malat1Δ2 mice show increased age-dependent retinal oxidative stress and corneal opacity, while Malat1Δ1 mice show no obvious phenotype. Collectively, this study reveals a physiological function of the lncRNA Malat1 3'-isoform during the aging process.
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Affiliation(s)
- Amr. R. Ghanam
- Hefei National Research Center for Physical Sciences at the Microscale, MOE Key Laboratory of Cellular Dynamics, CAS Key Laboratory of Brain Function and Disease, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230026, China
| | - Shengwei Ke
- Hefei National Research Center for Physical Sciences at the Microscale, MOE Key Laboratory of Cellular Dynamics, CAS Key Laboratory of Brain Function and Disease, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230026, China
- Department of Urology and Andrology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China
| | - Shujuan Wang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China
| | - Ramy Elgendy
- Department of Pharmacology, College of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Chenyao Xie
- Hefei National Research Center for Physical Sciences at the Microscale, MOE Key Laboratory of Cellular Dynamics, CAS Key Laboratory of Brain Function and Disease, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230026, China
| | - Siqi Wang
- Hefei National Research Center for Physical Sciences at the Microscale, MOE Key Laboratory of Cellular Dynamics, CAS Key Laboratory of Brain Function and Disease, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230026, China
| | - Ran Zhang
- Hefei National Research Center for Physical Sciences at the Microscale, MOE Key Laboratory of Cellular Dynamics, CAS Key Laboratory of Brain Function and Disease, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230026, China
| | - Min Wei
- Hefei National Research Center for Physical Sciences at the Microscale, MOE Key Laboratory of Cellular Dynamics, CAS Key Laboratory of Brain Function and Disease, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230026, China
| | - Weiguang Liu
- Hefei National Research Center for Physical Sciences at the Microscale, MOE Key Laboratory of Cellular Dynamics, CAS Key Laboratory of Brain Function and Disease, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230026, China
| | - Jun Cao
- Hefei National Research Center for Physical Sciences at the Microscale, MOE Key Laboratory of Cellular Dynamics, CAS Key Laboratory of Brain Function and Disease, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230026, China
| | - Yan Zhang
- Stroke Center & Department of Neurology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Zhi Zhang
- Hefei National Research Center for Physical Sciences at the Microscale, MOE Key Laboratory of Cellular Dynamics, CAS Key Laboratory of Brain Function and Disease, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230026, China
| | - Tian Xue
- Hefei National Research Center for Physical Sciences at the Microscale, MOE Key Laboratory of Cellular Dynamics, CAS Key Laboratory of Brain Function and Disease, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230026, China
| | - Yong Zheng
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China
| | - Xiaoyuan Song
- Hefei National Research Center for Physical Sciences at the Microscale, MOE Key Laboratory of Cellular Dynamics, CAS Key Laboratory of Brain Function and Disease, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230026, China
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Oto T, Urata K, Hayashi Y, Hitomi S, Shibuta I, Iwata K, Iinuma T, Shinoda M. Age-Related Differences in Transient Receptor Potential Vanilloid 1 and 2 Expression Patterns in the Trigeminal Ganglion Neurons Contribute to Changes in the Palatal Mucosal Heat Pain Sensitivity. TOHOKU J EXP MED 2022; 256:283-290. [PMID: 35296569 DOI: 10.1620/tjem.2022.j004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Affiliation(s)
- Tatsuki Oto
- Department of Complete Denture Prosthodontics, Nihon University School of Dentistry
| | - Kentaro Urata
- Department of Complete Denture Prosthodontics, Nihon University School of Dentistry
| | | | - Suzuro Hitomi
- Department of Physiology, Nihon University School of Dentistry
| | - Ikuko Shibuta
- Department of Physiology, Nihon University School of Dentistry
| | - Koichi Iwata
- Department of Physiology, Nihon University School of Dentistry
| | - Toshimitsu Iinuma
- Department of Complete Denture Prosthodontics, Nihon University School of Dentistry
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Cao B, Zeng M, Si Y, Zhang B, Wang Y, Xu R, Huang Y, Feng W, Zheng X. Extract of Corallodiscus flabellata attenuates renal fibrosis in SAMP8 mice via the Wnt/β-catenin/RAS signaling pathway. BMC Complement Med Ther 2022; 22:52. [PMID: 35227255 PMCID: PMC8887028 DOI: 10.1186/s12906-022-03535-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 02/22/2022] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Fibrosis is one of the most common pathological features of the aging process of the kidney, and fibrosis in aging kidneys also aggravates the process of chronic kidney disease (CKD). Corallodiscus flabellata B. L. Burtt (C. flabellata, CF) is a commonly used botanical drug in Chinese folklore. However, few studies have reported its pharmacological effects. This study aimed to explore the effect of CF ethanol extract on renal fibrosis in SAMP8 mice and identify potentially active compounds. METHODS Senescence-accelerated mouse-prone 8 (SAMP8) were used as animal models, and different doses of CF were given by gavage for one month. To observe the degree of renal aging in mice using β-galactosidase staining. Masson staining and the expression levels of Col-I, α-SMA, and FN were used to evaluate the renal fibrosis in mice. The protein expression levels of Nrf2 pathway and Wnt/β-catenin/RAS pathway in the kidney were measured. And β-galactosidase (β-gal) induced NRK-52E cells as an in vitro model to screen the active components of CF. RESULTS The CF ethanol extract significantly inhibited the activity of renal β-galactosidase and the expression levels of Col-I, α-SMA, and FN in SAMP8 mice, and improved Masson staining in SAMP8 mice. CF remarkably reduced urinary protein, creatinine, urea nitrogen and serum levels of TNF-α and IL-1β in SAMP8 mice, and significantly increased the levels of SOD and GSH-Px. Moreover, CF activated the Nrf2 pathway and blocked the Wnt/β-catenin/RAS pathway in the kidneys of mice. Besides, 3,4-dihydroxyphenylethanol (SDC-0-14, 16) and (3,4-dihydroxyphenylethanol-8-O-[4-O-trans-caffeoyl-β-D-apiofuranosyl-(1→3)-β-D-glucopyranosyl (1→6)]-β-D-glucopyranoside (SDC-1-8) were isolated from CF, which reduced the senescence of NRK-52E cells, and maybe the active ingredients of CF playing the anti-aging role. CONCLUSIONS Our experiments illuminated that CF ethanol extract may ameliorate renal fibrosis in SAMP8 mice via the Wnt/β-catenin/RAS pathway. And SDC-0-14,16 and SDC-1-8 may be the material basis for CF to exert anti-renal senescence-related effects.
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Affiliation(s)
- Bing Cao
- Henan University of Chinese Medicine, 450046, Zhengzhou, China
- The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 450046, Zhengzhou, China
| | - Mengnan Zeng
- Henan University of Chinese Medicine, 450046, Zhengzhou, China
- The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 450046, Zhengzhou, China
| | - Yanpo Si
- Henan University of Chinese Medicine, 450046, Zhengzhou, China
- The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 450046, Zhengzhou, China
| | - Beibei Zhang
- Henan University of Chinese Medicine, 450046, Zhengzhou, China
- The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 450046, Zhengzhou, China
| | - Yangyang Wang
- Henan University of Chinese Medicine, 450046, Zhengzhou, China
- The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 450046, Zhengzhou, China
| | - Ruiqi Xu
- Henan University of Chinese Medicine, 450046, Zhengzhou, China
- The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 450046, Zhengzhou, China
| | - Yanjie Huang
- Henan University of Chinese Medicine, 450046, Zhengzhou, China
- The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 450046, Zhengzhou, China
| | - Weisheng Feng
- Henan University of Chinese Medicine, 450046, Zhengzhou, China
- The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 450046, Zhengzhou, China
| | - Xiaoke Zheng
- Henan University of Chinese Medicine, 450046, Zhengzhou, China.
- The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 450046, Zhengzhou, China.
- School of Pharmacy, Henan University of Chinese Medicine, 156 Jinshui East Road, 450046, Zhengzhou, China.
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11
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Nagaoka N, Kawanokuchi J, Takagi K, Yamamoto T, Ishida T, Ma N. Observation of Acupuncture Effects on the Expression of Taurine Transporter and Taurine in the Senescence-Accelerated Mouse Brain: A Pilot Study. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1370:341-350. [DOI: 10.1007/978-3-030-93337-1_33] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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12
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Baek KW, Jung YK, Park JS, Kim JS, Hah YS, Kim SJ, Yoo JI. Two Types of Mouse Models for Sarcopenia Research: Senescence Acceleration and Genetic Modification Models. J Bone Metab 2021; 28:179-191. [PMID: 34520651 PMCID: PMC8441530 DOI: 10.11005/jbm.2021.28.3.179] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 06/03/2021] [Indexed: 12/13/2022] Open
Abstract
Sarcopenia leads to loss of skeletal muscle mass, quality, and strength due to aging; it was recently given a disease code (International Classification of Diseases, Tenth Revision, Clinical Modification, M62.84). As a result, in recent years, sarcopenia-related research has increased. In addition, various studies seeking to prevent and treat sarcopenia by identifying the various mechanisms related to the reduction of skeletal muscle properties have been conducted. Previous studies have identified muscle synthesis and breakdown; investigating them has generated evidence for preventing and treating sarcopenia. Mouse models are still the most useful ones for determining mechanisms underlying sarcopenia through correlations and interventions involving specific genes and their phenotypes. Mouse models used to study sarcopenia often induce muscle atrophy by hindlimb unloading, denervation, or immobilization. Though it is less frequently used, the senescence-accelerated mouse can also be useful for sarcopenia research. Herein, we discuss cases where senescence-accelerated and genetically engineered mouse models were used in sarcopenia research and different perspectives to use them.
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Affiliation(s)
- Kyung-Wan Baek
- Department of Physical Education, Gyeongsang National University, Jinju, Korea.,Department of Orthopaedic Surgery, Gyeongsang National University Hospital, Gyeongsang National University, Jinju, Korea
| | - Youn-Kwan Jung
- Biomedical Research Institute, Gyeongsang National University Hospital, Gyeongsang National University, Jinju, Korea
| | - Jin Sung Park
- Department of Orthopaedic Surgery and Institute of Health Sciences, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Korea
| | - Ji-Seok Kim
- Department of Physical Education, Gyeongsang National University, Jinju, Korea
| | - Young-Sool Hah
- Biomedical Research Institute, Gyeongsang National University Hospital, Gyeongsang National University, Jinju, Korea
| | - So-Jeong Kim
- Department of Convergence Medical Science, Gyeongsang National University, Jinju, Korea
| | - Jun-Il Yoo
- Department of Orthopaedic Surgery, Gyeongsang National University Hospital, Gyeongsang National University, Jinju, Korea
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13
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Fusco-Allison G, Li DK, Hunter B, Jackson D, Bannon PG, Lal S, O'Sullivan JF. Optimizing the discovery and assessment of therapeutic targets in heart failure with preserved ejection fraction. ESC Heart Fail 2021; 8:3643-3655. [PMID: 34342166 PMCID: PMC8497375 DOI: 10.1002/ehf2.13504] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 06/02/2021] [Accepted: 06/21/2021] [Indexed: 01/09/2023] Open
Abstract
There is an urgent need for models that faithfully replicate heart failure with preserved ejection fraction (HFpEF), now recognized as the most common form of heart failure in the world. In vitro approaches have several shortcomings, most notably the immature nature of stem cell‐derived human cardiomyocytes [induced pluripotent stem cells (iPSC)] and the relatively short lifespan of primary cardiomyocytes. Three‐dimensional ‘organoids’ incorporating mature iPSCs with other cell types such as endothelial cells and fibroblasts are a significant advance, but lack the complexity of true myocardium. Animal models can replicate many features of human HFpEF, and rodent models are the most common, and recent attempts to incorporate haemodynamic, metabolic, and ageing contributions are encouraging. Differences relating to species, physiology, heart rate, and heart size are major limitations for rodent models. Porcine models mitigate many of these shortcomings and approximate human physiology more closely, but cost and time considerations limit their potential for widespread use. Ex vivo analysis of failing hearts from animal models offer intriguing possibilities regarding cardiac substrate utilisation, but are ultimately subject to the same constrains as the animal models from which the hearts are obtained. Ex vivo approaches using human myocardial biopsies can uncover new insights into pathobiology leveraging myocardial energetics, substrate turnover, molecular changes, and systolic/diastolic function. In collaboration with a skilled cardiothoracic surgeon, left ventricular endomyocardial biopsies can be obtained at the time of valvular surgery in HFpEF patients. Critically, these tissues maintain their disease phenotype, preserving inter‐relationship of myocardial cells and extracellular matrix. This review highlights a novel approach, where ultra‐thin myocardial tissue slices from human HFpEF hearts can be used to assess changes in myocardial structure and function. We discuss current approaches to modelling HFpEF, describe in detail the novel tissue slice model, expand on exciting opportunities this model provides, and outline ways to improve this model further.
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Affiliation(s)
- Gabrielle Fusco-Allison
- Precision Cardiovascular Laboratory, The University of Sydney, Sydney, New South Wales, Australia.,Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia.,Heart Research Institute, Newtown, Sydney, New South Wales, Australia.,Central Clinical School, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Desmond K Li
- Precision Cardiovascular Laboratory, The University of Sydney, Sydney, New South Wales, Australia.,Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia.,Heart Research Institute, Newtown, Sydney, New South Wales, Australia.,Central Clinical School, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Benjamin Hunter
- Precision Cardiovascular Laboratory, The University of Sydney, Sydney, New South Wales, Australia.,Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia.,School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.,Central Clinical School, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Dan Jackson
- Precision Cardiovascular Laboratory, The University of Sydney, Sydney, New South Wales, Australia.,Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia.,Central Clinical School, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.,Discipline of Surgery, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Paul G Bannon
- Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia.,Discipline of Surgery, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Sean Lal
- Precision Cardiovascular Laboratory, The University of Sydney, Sydney, New South Wales, Australia.,Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia.,School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.,Central Clinical School, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.,Department of Cardiology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
| | - John F O'Sullivan
- Precision Cardiovascular Laboratory, The University of Sydney, Sydney, New South Wales, Australia.,Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia.,Heart Research Institute, Newtown, Sydney, New South Wales, Australia.,Central Clinical School, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.,Department of Cardiology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.,Faculty of Medicine, TU Dresden, Dresden, Germany
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14
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Rosell-Cardona C, Griñan-Ferré C, Pérez-Bosque A, Polo J, Pallàs M, Amat C, Moretó M, Miró L. Dietary Spray-Dried Porcine Plasma Reduces Neuropathological Alzheimer's Disease Hallmarks in SAMP8 Mice. Nutrients 2021; 13:2369. [PMID: 34371878 PMCID: PMC8308893 DOI: 10.3390/nu13072369] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 07/04/2021] [Accepted: 07/08/2021] [Indexed: 12/12/2022] Open
Abstract
Alzheimer's disease (AD) is characterized by the aberrant processing of amyloid precursor protein (APP) and the accumulation of hyperphosphorylated tau, both of which are accompanied by neuroinflammation. Dietary supplementation with spray-dried porcine plasma (SDP) has anti-inflammatory effects in inflammation models. We investigated whether dietary supplementation with SDP prevents the neuropathological features of AD. The experiments were performed in 2- and 6-month-old SAMP8 mice fed a control diet, or a diet supplemented with 8% SDP, for 4 months. AD brain molecular markers were determined by Western blot and real-time PCR. Senescent mice showed reduced levels of p-GSK3β (Ser9) and an increase in p-CDK5, p-tau (Ser396), sAPPβ, and the concentration of Aβ40, (all p < 0.05). SDP prevented these effects of aging and reduced Bace1 levels (all p < 0.05). Senescence increased the expression of Mme1 and Ide1 and pro-inflammatory cytokines (Il-17 and Il-18; all p < 0.05); these changes were prevented by SDP supplementation. Moreover, SDP increased Tgf-β expression (p < 0.05). Furthermore, in aged mice, the gene expression levels of the microglial activation markers Trem2, Ym1, and Arg1 were increased, and SDP prevented these increases (all p < 0.05). Thus, dietary SDP might delay AD onset by reducing its hallmarks in senescent mice.
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Affiliation(s)
- Cristina Rosell-Cardona
- Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, Institute for Nutrition and Food Safety, Universitat de Barcelona (UB), 08028 Barcelona, Spain; (C.R.-C.); (A.P.-B.); (C.A.); (M.M.)
| | - Christian Griñan-Ferré
- Department of Pharmacology, Toxicology, and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neurosciences, CIBERNED, Universitat de Barcelona (UB), 08028 Barcelona, Spain; (C.G.-F.); (M.P.)
| | - Anna Pérez-Bosque
- Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, Institute for Nutrition and Food Safety, Universitat de Barcelona (UB), 08028 Barcelona, Spain; (C.R.-C.); (A.P.-B.); (C.A.); (M.M.)
| | | | - Mercè Pallàs
- Department of Pharmacology, Toxicology, and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neurosciences, CIBERNED, Universitat de Barcelona (UB), 08028 Barcelona, Spain; (C.G.-F.); (M.P.)
| | - Concepció Amat
- Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, Institute for Nutrition and Food Safety, Universitat de Barcelona (UB), 08028 Barcelona, Spain; (C.R.-C.); (A.P.-B.); (C.A.); (M.M.)
| | - Miquel Moretó
- Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, Institute for Nutrition and Food Safety, Universitat de Barcelona (UB), 08028 Barcelona, Spain; (C.R.-C.); (A.P.-B.); (C.A.); (M.M.)
| | - Lluïsa Miró
- Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, Institute for Nutrition and Food Safety, Universitat de Barcelona (UB), 08028 Barcelona, Spain; (C.R.-C.); (A.P.-B.); (C.A.); (M.M.)
- APC Europe S.L.U., 08403 Granollers, Spain;
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15
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Saeki N, Inui-Yamamoto C, Kuraki M, Itoh S, Inubushi T, Okamoto M, Akiyama S, Wakisaka S, Abe M. Senescence-accelerated mouse prone 8 (SAMP8) mice exhibit reduced entoconid in the lower second molar. Arch Oral Biol 2021; 128:105172. [PMID: 34058725 DOI: 10.1016/j.archoralbio.2021.105172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 05/18/2021] [Accepted: 05/24/2021] [Indexed: 11/26/2022]
Abstract
OBJECTIVE The position and size of the major cusps in mammalian molars are arranged in a characteristic pattern that depends on taxonomy. In humans, the cusp which locates distally within each molar is smaller than the mesially located cusp, which is referred to as "distal reduction". Although this concept has been well-recognized, it is still unclear how this reduction occurs. Current study examined whether senescence-accelerating mouse prone 8 (SAMP8) mice could be a possible animal model for studying how the mammalian molar cusp size is determined. DESIGN SAMP8 mice were compared with parental control (SAMR1) mice. Microcomputed tomography images of young and aged mice were captured to observe molar cusp morphologies. Cusp height from cement-enamel junction and mesio-distal length of molars were measured. The statistical comparison of the measurements was performed by Mann-Whitney U test. RESULTS SAMP8 mice showed reduced development of the disto-lingual cusp (entoconid) of lower second molar when compared with SAMR1 mice. The enamel thickness and structure was disturbed at entoconid, and aged SAMP8 mice displayed severe wear of the entoconid in lower second molar. These phenotypes were observed on both sides of the lower second molar. CONCLUSIONS In addition to the general senescence phenotype observed in SAMP8 mice, this strain may genetically possess molar cusp phenotypes which is determined prenatally. Further, SAMP8 mice would be a potential model strain to study the genetic causes of the distal reduction of molar cusp size.
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Affiliation(s)
- Naoya Saeki
- Department of Oral Anatomy and Developmental Biology, Osaka University Graduate School of Dentistry, Yamada-oka 1-8, Suita, Osaka, Japan; Division of Special Care Dentistry, Osaka University Dental Hospital, Osaka, Japan
| | - Chizuko Inui-Yamamoto
- Department of Oral Anatomy and Developmental Biology, Osaka University Graduate School of Dentistry, Yamada-oka 1-8, Suita, Osaka, Japan
| | - Moe Kuraki
- Department of Oral Anatomy and Developmental Biology, Osaka University Graduate School of Dentistry, Yamada-oka 1-8, Suita, Osaka, Japan
| | - Shousaku Itoh
- Department of Restorative Dentistry and Endodontology, Osaka University Graduate School of Dentistry, Osaka, Japan
| | - Toshihiro Inubushi
- Department of Orthodontics and Dentofacial Orthopedics, Osaka University Graduate School of Dentistry, Osaka, Japan
| | - Motoki Okamoto
- Department of Restorative Dentistry and Endodontology, Osaka University Graduate School of Dentistry, Osaka, Japan
| | - Shigehisa Akiyama
- Division of Special Care Dentistry, Osaka University Dental Hospital, Osaka, Japan
| | - Satoshi Wakisaka
- Department of Oral Anatomy and Developmental Biology, Osaka University Graduate School of Dentistry, Yamada-oka 1-8, Suita, Osaka, Japan
| | - Makoto Abe
- Department of Oral Anatomy and Developmental Biology, Osaka University Graduate School of Dentistry, Yamada-oka 1-8, Suita, Osaka, Japan.
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16
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Molina-Martínez P, Corpas R, García-Lara E, Cosín-Tomás M, Cristòfol R, Kaliman P, Solà C, Molinuevo JL, Sánchez-Valle R, Antonell A, Lladó A, Sanfeliu C. Microglial Hyperreactivity Evolved to Immunosuppression in the Hippocampus of a Mouse Model of Accelerated Aging and Alzheimer's Disease Traits. Front Aging Neurosci 2021; 12:622360. [PMID: 33584248 PMCID: PMC7875867 DOI: 10.3389/fnagi.2020.622360] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 12/31/2020] [Indexed: 12/13/2022] Open
Abstract
Neuroinflammation is a risk factor for Alzheimer's disease (AD). We sought to study the glial derangement in AD using diverse experimental models and human brain tissue. Besides classical pro-inflammatory cytokines, we analyzed chitinase 3 like 1 (CHI3L1 or YKL40) and triggering receptor expressed on myeloid cells 2 (TREM2) that are increasingly being associated with astrogliosis and microgliosis in AD, respectively. The SAMP8 mouse model of accelerated aging and AD traits showed elevated pro-inflammatory cytokines and activated microglia phenotype. Furthermore, 6-month-old SAMP8 showed an exacerbated inflammatory response to peripheral lipopolysaccharide in the hippocampus and null responsiveness at the advanced age (for this strain) of 12 months. Gene expression of TREM2 was increased in the hippocampus of transgenic 5XFAD mice and in the cingulate cortex of autosomal dominant AD patients, and to a lesser extent in aged SAMP8 mice and sporadic early-onset AD patients. However, gene expression of CHI3L1 was increased in mice but not in human AD brain samples. The results support the relevance of microglia activation in the pathways leading to neurodegeneration and suggest diverse neuroinflammatory responses according to the AD process. Therefore, the SAMP8 mouse model with marked alterations in the dynamics of microglia activation and senescence may provide a complementary approach to transgenic mouse models for the study of the neuroinflammatory mechanisms underlying AD risk and progression.
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Affiliation(s)
- Patricia Molina-Martínez
- Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain
| | - Rubén Corpas
- Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain.,Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Elisa García-Lara
- Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain.,Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Marta Cosín-Tomás
- Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain
| | - Rosa Cristòfol
- Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain
| | - Perla Kaliman
- Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain.,Faculty of Health Sciences, Universitat Oberta de Catalunya, Barcelona, Spain
| | - Carme Solà
- Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain.,Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - José Luis Molinuevo
- Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Alzheimer's Disease and Other Cognitive Disorders Unit, Department of Neurology, Hospital Clínic, Barcelona, Spain.,Fundació Clínic per a la Recerca Biomèdica, Universitat de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain
| | - Raquel Sánchez-Valle
- Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Alzheimer's Disease and Other Cognitive Disorders Unit, Department of Neurology, Hospital Clínic, Barcelona, Spain.,Fundació Clínic per a la Recerca Biomèdica, Universitat de Barcelona, Barcelona, Spain
| | - Anna Antonell
- Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Alzheimer's Disease and Other Cognitive Disorders Unit, Department of Neurology, Hospital Clínic, Barcelona, Spain.,Fundació Clínic per a la Recerca Biomèdica, Universitat de Barcelona, Barcelona, Spain
| | - Albert Lladó
- Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain.,Alzheimer's Disease and Other Cognitive Disorders Unit, Department of Neurology, Hospital Clínic, Barcelona, Spain.,Fundació Clínic per a la Recerca Biomèdica, Universitat de Barcelona, Barcelona, Spain
| | - Coral Sanfeliu
- Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain.,Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain
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17
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Kubo KY, Ogasawara A, Tsugane H, Iinuma M, Takahashi T, Azuma K. Environmental enrichment improves hypomyelination, synaptic alterations, and memory deficits caused by tooth loss in aged SAMP8 mice. Arch Oral Biol 2021; 123:105039. [PMID: 33454419 DOI: 10.1016/j.archoralbio.2021.105039] [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: 09/07/2020] [Revised: 12/01/2020] [Accepted: 12/29/2020] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Prolonged mild stress due to tooth loss leads to morphologic and functional alterations of the hippocampus, as well as cognitive memory impairments in aged animals. An enriched environment improves stress-induced hippocampus-dependent cognitive impairments. The potential mechanisms underlying the beneficial effects of an enriched environment, however, remain unclear. In the present study, we investigated whether an enriched environment affects morphologic remodeling of the hippocampal myelin, synapses, and spatial learning deficits caused by tooth loss in aged senescence-accelerated mouse strain P8 (SAMP8) mice. DESIGN SAMP8 mice (8 months old) with either teeth intact or teeth extracted were raised in a standard or enriched environment for three weeks. Spatial learning and memory ability was evaluated in a Morris water maze test. The morphologic features of the myelin sheath and synapses in the hippocampus were investigated by electron microscopy. RESULTS Mice with tooth loss had a thinner myelin sheaths and shorter postsynaptic densities in the hippocampal CA1 region, and impaired hippocampus-dependent spatial learning ability. Exposure to an enriched environment ameliorated the hypomyelination and synaptic alterations, and spatial learning and memory impairments induced by tooth loss in aged SAMP8 mice. CONCLUSION Our findings indicate that an enriched environment ameliorates hippocampal hypomyelination and synapse morphologic abnormalities, as well as learning deficits induced by tooth loss in aged SAMP8 mice.
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Affiliation(s)
- Kin-Ya Kubo
- Graduate School of Human Life Science, Nagoya Women's University, 3-40 Shioji-cho, Mizuho-ku, Nagoya, Aichi, 467-8610, Japan.
| | - Akifumi Ogasawara
- Departments of Pediatric Dentistry, Asahi University School of Dentistry, 1851 Hozumi, Mizuho, Gifu, 501-0296, Japan
| | - Hiroko Tsugane
- Departments of Pediatric Dentistry, Asahi University School of Dentistry, 1851 Hozumi, Mizuho, Gifu, 501-0296, Japan
| | - Mitsuo Iinuma
- Departments of Pediatric Dentistry, Asahi University School of Dentistry, 1851 Hozumi, Mizuho, Gifu, 501-0296, Japan
| | - Toru Takahashi
- 10 Sue-machi, Kanazawa City, Ishikawa Prefecture, 920-1392, Faculty of Nutrition, Department of Nutrition, Kanazawa Gakuin University, Japan
| | - Kagaku Azuma
- Department of Anatomy, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyusyu, 807-8555, Japan
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18
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Zhao L, Liu JW, Kan BH, Shi HY, Yang LP, Liu XY. Acupuncture accelerates neural regeneration and synaptophysin production after neural stem cells transplantation in mice. World J Stem Cells 2020; 12:1576-1590. [PMID: 33505601 PMCID: PMC7789117 DOI: 10.4252/wjsc.v12.i12.1576] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 09/23/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Synaptophysin plays a key role in synaptic development and plasticity of neurons and is closely related to the cognitive process of Alzheimer's disease (AD) patients. Exogenous neural stem cells (NSCs) improve the damaged nerve function. The effects of Sanjiao acupuncture on cognitive impairment may be related to the regulation of the NSC microenvironment. AIM To explore the anti-dementia mechanism of acupuncture by regulating the NSC microenvironment. METHODS NSCs were isolated from pregnant senescence-accelerated mouse resistant 1 (SAMR1) mice, labeled with BrdU, and injected into the hippocampus of senescence-accelerated mouse prone 8 (SAMP8) mice. Eight-month-old senescence-accelerated mice (SAM) were randomly divided into six groups: SAMR1 (RC), SAMP8 (PC), sham transplantation (PS), NSC transplantation (PT), NSC transplantation with acupuncture (PTA), and NSC transplantation with non-acupoint acupuncture (PTN). Morris water maze test was used to study the learning and memory ability of mice after NSC transplantation. Hematoxylin-eosin staining and immunofluorescence were used to observe the his-topathological changes and NSC proliferation in mice. A co-culture model of hippocampal slices and NSCs was established in vitro, and the synaptophysin expression in the hippocampal microenvironment of mice was observed by flow cytometry after acupuncture treatment. RESULTS Morris water maze test showed significant cognitive impairment of learning and memory in 8-mo-old SAMP8, which improved in all the NSC transplantation groups. The behavioral change in the PTA group was stronger than those in the other two groups (P < 0.05). Histopathologically, the hippocampal structure was clear, the cell arrangement was dense and orderly, and the necrosis of cells in CA1 and CA3 areas was significantly reduced in the PTA group when compared with the PC group. The BrdU-positive proliferating cells were found in NSC hippocampal transplantation groups, and the number increased significantly in the PTA group than in the PT and PTN groups (P < 0.05). Flow cytometry showed that after co-culture of NSCs with hippocampal slices in vitro, the synaptophysin expression in the PC group decreased in comparison to the RC group, that in PT, PTA, and PTN groups increased as compared to the PC group, and that in the PTA group increased significantly as compared to the PTN group with acupoint-related specificity (P < 0.05). CONCLUSION Acupuncture may promote nerve regeneration and synaptogenesis in SAMP8 mice by regulating the microenvironment of NSC transplantation to improve the nerve activity and promote the recovery of AD-damaged cells.
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Affiliation(s)
- Lan Zhao
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
- Tianjin Key Laboratory of Acupuncture and Moxibustion, Tianjin 300381, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China.
| | - Jian-Wei Liu
- Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Bo-Hong Kan
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
- Tianjin Key Laboratory of Acupuncture and Moxibustion, Tianjin 300381, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Hui-Yan Shi
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
- Tianjin Key Laboratory of Acupuncture and Moxibustion, Tianjin 300381, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Lin-Po Yang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
| | - Xin-Yu Liu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
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19
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Riehle C, Bauersachs J. Small animal models of heart failure. Cardiovasc Res 2020; 115:1838-1849. [PMID: 31243437 PMCID: PMC6803815 DOI: 10.1093/cvr/cvz161] [Citation(s) in RCA: 147] [Impact Index Per Article: 29.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 04/30/2019] [Accepted: 06/24/2019] [Indexed: 12/11/2022] Open
Abstract
Heart disease is a major cause of death worldwide with increasing prevalence, which urges the development of new therapeutic strategies. Over the last few decades, numerous small animal models have been generated to mimic various pathomechanisms contributing to heart failure (HF). Despite some limitations, these animal models have greatly advanced our understanding of the pathogenesis of the different aetiologies of HF and paved the way to understanding the underlying mechanisms and development of successful treatments. These models utilize surgical techniques, genetic modifications, and pharmacological approaches. The present review discusses the strengths and limitations of commonly used small animal HF models, which continue to provide crucial insight and facilitate the development of new treatment strategies for patients with HF.
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Affiliation(s)
- Christian Riehle
- Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, Germany
| | - Johann Bauersachs
- Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, Germany
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20
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Noguchi M, Kitakaze T, Kobayashi Y, Mukai K, Harada N, Yamaji R. β-Cryptoxanthin Improves p62 Accumulation and Muscle Atrophy in the Soleus Muscle of Senescence-Accelerated Mouse-Prone 1 Mice. Nutrients 2020; 12:nu12082180. [PMID: 32708051 PMCID: PMC7468743 DOI: 10.3390/nu12082180] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 07/15/2020] [Accepted: 07/21/2020] [Indexed: 12/25/2022] Open
Abstract
We investigated the effects of β-cryptoxanthin on skeletal muscle atrophy in senescence-accelerated mouse-prone 1 (SAMP1) mice. For 15 weeks, SAMP1 mice were intragastrically administered vehicle or β-cryptoxanthin. At 35 weeks of age, the skeletal muscle mass in SAMP1 mice was reduced compared with that in control senescence-accelerated mouse-resistant 1 (SAMR1) mice. β-cryptoxanthin increased muscle mass with an increase in the size of muscle fibers in the soleus muscle of SAMP1 mice. The expressions of autophagy-related factors such as beclin-1, p62, LC3-I, and LC3-II were increased in the soleus muscle of SAMP1 mice; however, β-cryptoxanthin administration inhibited this increase. Unlike in SAMR1 mice, p62 was punctately distributed throughout the cytosol in the soleus muscle fibers of SAMP1 mice; however, β-cryptoxanthin inhibited this punctate distribution. The cross-sectional area of p62-positive fiber was smaller than that of p62-negative fiber, and the ratio of p62-positive fibers to p62-negative fibers was increased in SAMP1 mice. β-cryptoxanthin decreased this ratio in SAMP1 mice. Furthermore, β-cryptoxanthin decreased the autophagy-related factor expression in murine C2C12 myotube. The autophagy inhibitor bafilomycin A1, but not the proteasome inhibitor MG132, inhibited the β-cryptoxanthin-induced decrease in p62 and LC3-II expressions. These results indicate that β-cryptoxanthin inhibits the p62 accumulation in fibers and improves muscle atrophy in the soleus muscle of SAMP1 mice.
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Affiliation(s)
- Mari Noguchi
- Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan; (M.N.); (T.K.); (Y.K.); (N.H.)
| | - Tomoya Kitakaze
- Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan; (M.N.); (T.K.); (Y.K.); (N.H.)
| | - Yasuyuki Kobayashi
- Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan; (M.N.); (T.K.); (Y.K.); (N.H.)
| | - Katsuyuki Mukai
- Daicel Corporation, Konan, Minato-ku, Tokyo 108-0075, Japan;
| | - Naoki Harada
- Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan; (M.N.); (T.K.); (Y.K.); (N.H.)
| | - Ryoichi Yamaji
- Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan; (M.N.); (T.K.); (Y.K.); (N.H.)
- Correspondence: ; Tel.: +81-722-54-9453
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21
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Corpuz HM, Arimura M, Chawalitpong S, Miyazaki K, Sawaguchi M, Nakamura S, Katayama S. Oral Administration of Okara Soybean By-Product Attenuates Cognitive Impairment in a Mouse Model of Accelerated Aging. Nutrients 2019; 11:E2939. [PMID: 31816987 PMCID: PMC6950093 DOI: 10.3390/nu11122939] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 11/28/2019] [Accepted: 11/30/2019] [Indexed: 12/17/2022] Open
Abstract
The microbiota-gut-brain axis has attracted increasing attention in the last decade. Here, we investigated whether okara, a soybean by-product rich in dietary fiber, can attenuate cognitive impairment in senescence-accelerated mouse prone 8 (SAMP8) mice by altering gut microbial composition. Mice were fed either a standard diet, or a diet containing okara (7.5% or 15%, w/w) for 26 weeks. In the memory test, the 7.5% okara-fed mice showed a longer step-through latency and the 15% okara-fed mice had a short escape latency compared with control mice. The 15% okara-fed mice displayed decreased body weight, increased fecal weight, and altered cecal microbiota composition compared with the control group; however, there was no significant difference in the serum lactic acid and butyric acid levels among these mice groups. The 7.5% okara-fed mice had significantly higher NeuN intensity in the hippocampus compared with control mice. Furthermore, a decrease in inflammatory cytokine TNF- and an increase in brain-derived neurotrophic factor (BDNF) was observed in the 7.5% okara-fed group. The expression of synthesizing enzyme of acetylcholine was increased by the okara diets, and the acetylcholine level in the brain was higher in the 7.5% okara-fed group than in the control. These suggest that oral administration of okara could delay cognitive decline without drastically changing gut microbiota.
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Affiliation(s)
- Henry M. Corpuz
- Interdisciplinary Graduate School of Science and Technology, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano 3994598, Japan; (H.M.C.); (S.N.)
- Rice Chemistry and Food Science Division, Philippine Rice Research Institute, Maligaya, Science City of Muñoz, Nueva Ecija 3119, Philippines
| | - Misa Arimura
- Faculty of Agriculture, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano 3994598, Japan; (M.A.); (S.C.)
| | - Supatta Chawalitpong
- Faculty of Agriculture, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano 3994598, Japan; (M.A.); (S.C.)
| | - Keiko Miyazaki
- Misuzu Corporation Co., Ltd., 1606 Wakasato, Nagano City, Nagano 3800928, Japan; (K.M.); (M.S.)
| | - Makoto Sawaguchi
- Misuzu Corporation Co., Ltd., 1606 Wakasato, Nagano City, Nagano 3800928, Japan; (K.M.); (M.S.)
| | - Soichiro Nakamura
- Interdisciplinary Graduate School of Science and Technology, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano 3994598, Japan; (H.M.C.); (S.N.)
- Faculty of Agriculture, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano 3994598, Japan; (M.A.); (S.C.)
| | - Shigeru Katayama
- Interdisciplinary Graduate School of Science and Technology, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano 3994598, Japan; (H.M.C.); (S.N.)
- Faculty of Agriculture, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano 3994598, Japan; (M.A.); (S.C.)
- Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano 3994598, Japan
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22
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Arc-Chagnaud C, Millan F, Salvador-Pascual A, Correas A, Olaso-Gonzalez G, De la Rosa A, Carretero A, Gomez-Cabrera M, Viña J. Reversal of age-associated frailty by controlled physical exercise: The pre-clinical and clinical evidences. SPORTS MEDICINE AND HEALTH SCIENCE 2019; 1:33-39. [PMID: 35782461 PMCID: PMC9219339 DOI: 10.1016/j.smhs.2019.08.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Demographic aging is one of the most serious challenges facing our society. Although we live longer, we do not live better because it is considered that approximately 16–20% of our life is spent in late-life morbidity. Older people have the greatest risk of developing frailty increasing the risk of presenting various adverse health events such as low quality of life, disability, hospitalization and even death. Frail men and women over 65 years old have lower muscle quality and muscle mass and higher percentage of body fat than non-frail people of the same age. In this review we will address the main physiological changes in the muscular and nervous system associated to aging. More specifically we will review the changes in muscle mass, quality, and strength relating them with the decrease in capillarization and muscular oxidative capacity as well as with the alterations in protein synthesis in the muscle with aging. The last section of the manuscript will be devoted to the animal models of frailty and the indexes developed to measure frailty in these models. We will finally address the importance of exercise training as an intervention to delay or even reverse frailty.
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Affiliation(s)
- C. Arc-Chagnaud
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia and CIBERFES, Fundación Investigación Hospital Clínico Universitario/INCLIVA, Valencia, Spain
- INRA, UMR866 Dynamique Musculaire et Métabolisme, Université de Montpellier, F-34060, Montpellier, France
| | - F. Millan
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia and CIBERFES, Fundación Investigación Hospital Clínico Universitario/INCLIVA, Valencia, Spain
| | - A. Salvador-Pascual
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia and CIBERFES, Fundación Investigación Hospital Clínico Universitario/INCLIVA, Valencia, Spain
| | - A.G. Correas
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia and CIBERFES, Fundación Investigación Hospital Clínico Universitario/INCLIVA, Valencia, Spain
| | - G. Olaso-Gonzalez
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia and CIBERFES, Fundación Investigación Hospital Clínico Universitario/INCLIVA, Valencia, Spain
| | - A. De la Rosa
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia and CIBERFES, Fundación Investigación Hospital Clínico Universitario/INCLIVA, Valencia, Spain
| | - A. Carretero
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia and CIBERFES, Fundación Investigación Hospital Clínico Universitario/INCLIVA, Valencia, Spain
| | - M.C. Gomez-Cabrera
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia and CIBERFES, Fundación Investigación Hospital Clínico Universitario/INCLIVA, Valencia, Spain
- Corresponding author. Av. Blasco Ibañez 15, 46010, Valencia, Spain.
| | - J. Viña
- Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia and CIBERFES, Fundación Investigación Hospital Clínico Universitario/INCLIVA, Valencia, Spain
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23
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Lam V, Stephenson A, Nesbit M, Mamsa S, Hackett M, Takechi R, Mamo JCL. Chronic high fat feeding paradoxically attenuates cerebral capillary dysfunction and neurovascular inflammation in Senescence-Accelerated-Murine-Prone Strain 8 mice. Nutr Neurosci 2019; 24:635-643. [PMID: 31510891 DOI: 10.1080/1028415x.2019.1664533] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Background: A body of epidemiological, clinical and preclinical studies suggest increased risk for cerebro- and cardio-vascular disease associated with dietary ingestion of long-chain saturated fatty acids (LCSFA). In wild-type rodent models, chronic ingestion of LCSFA diets are associated with increased cerebral capillary permeability, heightened neurovascular inflammation and poorer cognitive performance. However, recent studies suggest that diets enriched in fat may paradoxically attenuate elements of the ageing phenotype via a caloric support axis.Objective: The purpose of this study was to explore the effects of dietary LCSFA on cerebral capillary integrity and neurovascular inflammation in an established model of accelerated ageing, Senescence-Accelerated-Murine-Prone Strain 8 (SAMP8) mice.Methods: From 6 weeks of age, SAMP8 mice and age-matched controls were randomised to either normal chow, or to an LCSFA-enriched diet, for either 12 or 34 weeks. An additional group of SAMP8 mice were provided the LCSFA-enriched diet for 12 weeks followed by the provision of ordinary low-fat chow for 22 weeks. Ex vivo measures of cerebrovascular integrity, neurovascular inflammation and astrocytic activation, were determined via 3-dimensional immunofluorescent confocal microscopy methodologies.Results: LCSFA-fed SAMP8 mice had markedly attenuated cerebral capillary dysfunction concomitant with reduced microglial activation. In SAMP8 mice transiently maintained on an LCSFA diet for 12 weeks, suppression of neurovascular inflammation persisted. Marked hippocampal astrogliosis was evident in LCSFA-fed mice when compared to SAMP8 mice maintained on ordinary chow.Conclusion: The findings from this study support the notion that high-fat, potentially ketogenic diets, may confer neuroprotection in SAMP8 mice through a vascular-support axis.
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Affiliation(s)
- Virginie Lam
- Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin University, Perth, WA, Australia.,School of Public Health, Faculty of Health Sciences, Curtin University, Perth, WA, Australia
| | - Andrea Stephenson
- Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin University, Perth, WA, Australia.,School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Perth, WA, Australia
| | - Michael Nesbit
- Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin University, Perth, WA, Australia.,School of Public Health, Faculty of Health Sciences, Curtin University, Perth, WA, Australia
| | - Somayra Mamsa
- Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin University, Perth, WA, Australia
| | - Mark Hackett
- Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin University, Perth, WA, Australia.,School of Molecular and Life Sciences, Faculty of Science and Engineering, Curtin University, Perth, WA, Australia
| | - Ryusuke Takechi
- Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin University, Perth, WA, Australia.,School of Public Health, Faculty of Health Sciences, Curtin University, Perth, WA, Australia
| | - John C L Mamo
- Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin University, Perth, WA, Australia.,School of Public Health, Faculty of Health Sciences, Curtin University, Perth, WA, Australia
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24
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Chou MY, Chen YJ, Lin LH, Nakao Y, Lim AL, Wang MF, Yong SM. Protective Effects of Hydrolyzed Chicken Extract (Probeptigen®/Cmi-168) on Memory Retention and Brain Oxidative Stress in Senescence-Accelerated Mice. Nutrients 2019; 11:E1870. [PMID: 31408929 PMCID: PMC6722682 DOI: 10.3390/nu11081870] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 08/02/2019] [Accepted: 08/06/2019] [Indexed: 02/07/2023] Open
Abstract
The senescence-accelerated prone (SAMP8) mouse model shows age-dependent deterioration in learning and memory and increased oxidative stress in the brain. We previously showed that healthy subjects on a six-week supplementation of a chicken meat hydrolysate (ProBeptigen®/CMI-168) demonstrated enhanced and sustained cognitive performance up until two weeks after the termination of supplementation. In this study, we investigate the effect of ProBeptigen on the progression of age-related cognitive decline. Three-month old SAMP8 mice were orally administered different doses of ProBeptigen (150,300 or 600 mg/kg/day) or saline daily for 13 weeks. Following ProBeptigen supplementation, mice showed lower scores of senescence and improved learning and memory in avoidance tasks. ProBeptigen treatment also increased antioxidant enzyme activity and dopamine level while reducing protein and lipid peroxidation and mitochondrial DNA damage in the brain. Microarray analysis of hippocampus revealed several processes that may be involved in the improvement of cognitive ability by ProBeptigen, including heme binding, insulin growth factor (IGF) regulation, carboxylic metabolic process, oxidation-reduction process and endopeptidase inhibition. Genes found to be significantly altered in both ProBeptigen treated male and female mice include Mup1, Mup17, Mup21, Ahsg and Alb. Taken together, these results suggest a potential anti-aging effect of ProBeptigen in alleviating cognitive deficits and promoting the antioxidant defense system.
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Affiliation(s)
- Ming-Yu Chou
- Department of Food and Nutrition, Providence University, Taichung 43301, Taiwan
- Quanzhou Preschool Education College, Quanzhou 362000, China
| | - Ying-Ju Chen
- Department of Food and Nutrition, Providence University, Taichung 43301, Taiwan
| | - Liang-Hung Lin
- Department of Food and Nutrition, Providence University, Taichung 43301, Taiwan
| | - Yoshihiro Nakao
- Scientific Research and Applications, BRAND'S Suntory Asia, Singapore 048423, Singapore
| | - Ai Lin Lim
- Scientific Research and Applications, BRAND'S Suntory Asia, Singapore 048423, Singapore
| | - Ming-Fu Wang
- Department of Food and Nutrition, Providence University, Taichung 43301, Taiwan.
| | - Shan May Yong
- Scientific Research and Applications, BRAND'S Suntory Asia, Singapore 048423, Singapore.
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25
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Katayama S, Nakamura S. Emerging roles of bioactive peptides on brain health promotion. Int J Food Sci Technol 2018. [DOI: 10.1111/ijfs.14076] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Shigeru Katayama
- Department of Agriculture Graduate School of Science and Technology Shinshu University 8304 Minamiminowa Kamiina Nagano 399‐4598 Japan
| | - Soichiro Nakamura
- Department of Agriculture Graduate School of Science and Technology Shinshu University 8304 Minamiminowa Kamiina Nagano 399‐4598 Japan
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26
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Fimognari N, Hollings A, Lam V, Tidy RJ, Kewish CM, Albrecht MA, Takechi R, Mamo JCL, Hackett MJ. Biospectroscopic Imaging Provides Evidence of Hippocampal Zn Deficiency and Decreased Lipid Unsaturation in an Accelerated Aging Mouse Model. ACS Chem Neurosci 2018; 9:2774-2785. [PMID: 29901988 DOI: 10.1021/acschemneuro.8b00193] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Western society is facing a health epidemic due to the increasing incidence of dementia in aging populations, and there are still few effective diagnostic methods, minimal treatment options, and no cure. Aging is the greatest risk factor for memory loss that occurs during the natural aging process, as well as being the greatest risk factor for neurodegenerative disease such as Alzheimer's disease. Greater understanding of the biochemical pathways that drive a healthy aging brain toward dementia (pathological aging or Alzheimer's disease), is required to accelerate the development of improved diagnostics and therapies. Unfortunately, many animal models of dementia model chronic amyloid precursor protein overexpression, which although highly relevant to mechanisms of amyloidosis and familial Alzheimer's disease, does not model well dementia during the natural aging process. A promising animal model reported to model mechanisms of accelerated natural aging and memory impairments, is the senescence accelerated murine prone strain 8 (SAMP8), which has been adopted by many research group to study the biochemical transitions that occur during brain aging. A limitation to traditional methods of biochemical characterization is that many important biochemical and elemental markers (lipid saturation, lactate, transition metals) cannot be imaged at meso- or microspatial resolution. Therefore, in this investigation, we report the first multimodal biospectroscopic characterization of the SAMP8 model, and have identified important biochemical and elemental alterations, and colocalizations, between 4 month old SAMP8 mice and the relevant control (SAMR1) mice. Specifically, we demonstrate direct evidence of Zn deficiency within specific subregions of the hippocampal CA3 sector, which colocalize with decreased lipid unsaturation. Our findings also revealed colocalization of decreased lipid unsaturation and increased lactate in the corpus callosum white matter, adjacent to the hippocampus. Such findings may have important implication for future research aimed at elucidating specific biochemical pathways for therapeutic intervention.
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Affiliation(s)
- Nicholas Fimognari
- Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia
- School of Biomedical Sciences, Curtin University, Bentley, WA 6102, Australia
| | - Ashley Hollings
- Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia
- Curtin Institute for Functional Molecules and Interfaces, School of Molecular and Life Science, Curtin University, Bentley, WA 6845, Australia
| | - Virginie Lam
- Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia
- School of Public Health, Curtin University, Bentley, WA 6102, Australia
| | - Rebecca J. Tidy
- Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia
- Curtin Institute for Functional Molecules and Interfaces, School of Molecular and Life Science, Curtin University, Bentley, WA 6845, Australia
| | - Cameron M. Kewish
- Australian Nuclear Science and Technology Organisation, 800 Blackburn Road, Clayton, VIC 3168, Australia
| | - Matthew A. Albrecht
- Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia
| | - Ryu Takechi
- Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia
- School of Public Health, Curtin University, Bentley, WA 6102, Australia
| | - John C. L. Mamo
- Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia
- School of Public Health, Curtin University, Bentley, WA 6102, Australia
| | - Mark J. Hackett
- Curtin Health Innovation Research Institute, Curtin University, Bentley, WA 6102, Australia
- Curtin Institute for Functional Molecules and Interfaces, School of Molecular and Life Science, Curtin University, Bentley, WA 6845, Australia
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27
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Viña J, Borras C, Gomez-Cabrera MC. A free radical theory of frailty. Free Radic Biol Med 2018; 124:358-363. [PMID: 29958933 DOI: 10.1016/j.freeradbiomed.2018.06.028] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 06/21/2018] [Accepted: 06/25/2018] [Indexed: 12/18/2022]
Abstract
The free radical theory of ageing provided an intellectual framework for many laboratories working on ageing. However, experimental and clinical evidence showing that high doses of antioxidants do not have an effect on ageing or on age-associated diseases, cast doubts on the validity of this theory. Data from our own laboratory show that oxidative damage does not correlate with age, especially in the geriatric population, but rather with the frailty state. This has led us to postulate the free radical theory of frailty that proposes that oxidative damage is associated with frailty, but not with chronological age itself. Superoxide dismutase deficient mice are more frail than controls. But more importantly, we have observed that animals that are protected against oxidative damage by overexpression of antioxidant enzymes, delay the onset of frailty and are more vigorous than controls. In this review, we describe results from both, experimental animals and human cohorts, that lead us to the formulate this free radical theory of frailty.
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Affiliation(s)
- Jose Viña
- Freshage Research Group. Department of Physiology, Faculty of Medicine, University of Valencia, CIBERFES, INCLIVA, Avenida Blasco Ibañez, 15, Valencia, Spain
| | - Consuelo Borras
- Freshage Research Group. Department of Physiology, Faculty of Medicine, University of Valencia, CIBERFES, INCLIVA, Avenida Blasco Ibañez, 15, Valencia, Spain.
| | - Mari Carmen Gomez-Cabrera
- Freshage Research Group. Department of Physiology, Faculty of Medicine, University of Valencia, CIBERFES, INCLIVA, Avenida Blasco Ibañez, 15, Valencia, Spain
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28
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Vela S, Sainz N, Moreno-Aliaga MJ, Solas M, Ramirez MJ. DHA Selectively Protects SAMP-8-Associated Cognitive Deficits Through Inhibition of JNK. Mol Neurobiol 2018; 56:1618-1627. [PMID: 29911253 DOI: 10.1007/s12035-018-1185-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 06/07/2018] [Indexed: 12/15/2022]
Abstract
A potential role of marine n-3 polyunsaturated fatty acids (ω-3 PUFAs) has been suggested in memory, learning, and cognitive processes. Therefore, ω-3 PUFAs might be a promising treatment option, albeit controversial, for Alzheimer's disease (AD). Among the different mechanisms that have been proposed as responsible for the beneficial effects of ω-3 PUFAs, inhibition of JNK stands as a particularly interesting candidate. In the present work, it has been studied whether the administration of two different PUFAs (docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)) and a DHA-derived specialized pro-resolving lipid mediator (MaR1) is able to reverse cognitive deficits in the senescence-accelerated mouse prone 8 (SAMP8) mouse model of sporadic AD. The novel object recognition test (NORT) test showed that recognition memory was significantly impaired in SAMP8 mice, as shown by a significantly decreased discrimination index that was reversed by MaR1 and DHA. In the retention phase of the Morris water maze (MWM) task, SAMP8 mice showed memory deficit that only DHA treatment was able to reverse. pJNK levels were significantly increased in the hippocampus of SAMP8 mice compared to SAMR1 mice, and only DHA treatment was able to significantly reverse these increased pJNK levels. Similar results were found when measuring c-Jun, the main JNK substrate. Consequently to the increases in tau phosphorylation after increased pJNK, it was checked that tau phosphorylation (PHF-1) was increased in SAMP mice, and this effect was reversed after DHA treatment. Altogether, DHA could represent a new approach for the treatment of AD through JNK inhibition.
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Affiliation(s)
- S Vela
- Department of Pharmacology and Toxicology, University of Navarra, Pamplona, Spain
| | - Neira Sainz
- Centre for Nutrition Research, University of Navarra, Pamplona, Spain
| | - María J Moreno-Aliaga
- Centre for Nutrition Research, University of Navarra, Pamplona, Spain.,Department of Nutrition, Food Science and Physiology, University of Navarra, Pamplona, Spain.,CIBERobn, Physiopathology of Obesity and Nutrition, Institute of Health Carlos III (ISCIII), Madrid, Spain.,IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
| | - M Solas
- Department of Pharmacology and Toxicology, University of Navarra, Pamplona, Spain.,IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
| | - María J Ramirez
- Department of Pharmacology and Toxicology, University of Navarra, Pamplona, Spain. .,IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
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29
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Zhang SJ, Xu TT, Li L, Xu YM, Qu ZL, Wang XC, Huang SQ, Luo Y, Luo NC, Lu P, Shi YF, Yang X, Wang Q. Bushen-Yizhi formula ameliorates cognitive dysfunction through SIRT1/ER stress pathway in SAMP8 mice. Oncotarget 2018; 8:49338-49350. [PMID: 28521305 PMCID: PMC5564772 DOI: 10.18632/oncotarget.17638] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Accepted: 04/25/2017] [Indexed: 12/22/2022] Open
Abstract
The Chinese formula Bushen-Yizhi (BSYZ) has been reported to ameliorate cognitive dysfunction. However the mechanism is still unclear. In this study, we employ an aging model, SAMP8 mice, to explore whether BSYZ could protect dementia through SIRT1/endoplasmic reticulum (ER) stress pathway. Morris water maze and the fearing condition test results show that oral administration of BSYZ (1.46 g/kg/d, 2.92 g/kg/d and 5.84 g/kg/d) and donepezil (3 mg/kg/d) shorten the escape latency, increase the crossing times of the original position of the platform and the time spent in the target quadrant, and increase the freezing time. BSYZ decreases the activity of acetylcholinesterase (AChE), and increases the activity of choline acetyltransferase (ChAT) and the concentration of acetylcholine (Ach) in both hippocampus and cortex. In addition, western blot results (Bcl-2, Bax and Caspase-3) and TUNEL staining show that BSYZ prevents neuron from apoptosis, and elevates the expression of neurotrophic factors, including nerve growth factor (NGF), postsynapticdensity 95 (PSD95) and synaptophysin (SYN), in both hippocampus and cortex. BSYZ also increases the protein expression of SIRT1 and alleviates ER stress-associated proteins (PERK, IRE-1α, eIF-2α, BIP, PDI and CHOP). These results indicate that the neuroprotective mechanism of BSYZ might be related with SIRT1/ER stress pathway.
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Affiliation(s)
- Shi-Jie Zhang
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Ting-Ting Xu
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Lin Li
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Yu-Min Xu
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Zi-Ling Qu
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Xin-Chen Wang
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Shui-Qing Huang
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Yi Luo
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Na-Chuan Luo
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Ping Lu
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Ya-Fei Shi
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Xin Yang
- Department of Pharmacy, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510700, China
| | - Qi Wang
- Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
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Guo Y, Zhao Y, Nan Y, Wang X, Chen Y, Wang S. (-)-Epigallocatechin-3-gallate ameliorates memory impairment and rescues the abnormal synaptic protein levels in the frontal cortex and hippocampus in a mouse model of Alzheimer's disease. Neuroreport 2018; 28:590-597. [PMID: 28520620 DOI: 10.1097/wnr.0000000000000803] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
(-)-Epigallocatechin-3-gallate (EGCG) is the most abundant polyphenolic extract in green tea and it has attracted increasing attention for its multiple bioactive effects. However, the mechanisms by which EGCG exerts its neuroprotective actions in Alzheimer's disease (AD) are presently lacking. In the present study, a sporadic AD transgenic mouse model known as senescence-accelerated mouse prone 8 (SAMP8) was used to investigate whether oral administration of EGCG could improve recognition and memory function through reduction of amyloid β (Aβ) and tau hyperphosphorylation. We also investigated the effects of chronic EGCG treatment on the synaptic dysfunction in the frontal cortex (FC) and the hippocampus (Hip) of AD mice. The results showed that long-term oral consumption of EGCG at a relatively high dose (15 mg/kg) improved memory function in SAMP8 mice in the Y-maze and Morris water maze. The levels of Aβ1-42 and BACE-1 in FC and Hip were significantly reduced by EGCG treatment. EGCG treatment also prevented the hyperphosphorylation of tau and reversed the decreased synaptic protein marker synaptophysin and postsynaptic density protein 95 in FC and Hip of SAMP8 mice. The present study suggests that long-term oral consumption of EGCG ameliorates impairments in spatial learning and memory and rescues the reduction in synaptic proteins observed in an AD mouse model. Thus, EGCG may represent a novel candidate agent for the treatment of neurodegenerative diseases.
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Affiliation(s)
- Yufang Guo
- Department of Pathophysiology, Institute of Basic Medicine Science, Xi'an Medical University, Xi'an, China
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Sirac C, Herrera GA, Sanders PW, Batuman V, Bender S, Ayala MV, Javaugue V, Teng J, Turbat-Herrera EA, Cogné M, Touchard G, Leung N, Bridoux F. Animal models of monoclonal immunoglobulin-related renal diseases. Nat Rev Nephrol 2018; 14:246-264. [DOI: 10.1038/nrneph.2018.8] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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Virgili J, Lebbadi M, Tremblay C, St-Amour I, Pierrisnard C, Faucher-Genest A, Emond V, Julien C, Calon F. Characterization of a 3xTg-AD mouse model of Alzheimer's disease with the senescence accelerated mouse prone 8 (SAMP8) background. Synapse 2018; 72. [DOI: 10.1002/syn.22025] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Revised: 01/11/2018] [Accepted: 01/16/2018] [Indexed: 12/20/2022]
Affiliation(s)
- Jessica Virgili
- Faculté de Pharmacie; Université Laval; Quebec Canada
- Axe Neurosciences, Centre de Recherche du CHU de Québec; Université Laval; Québec Canada
| | - Meryem Lebbadi
- Faculté de Pharmacie; Université Laval; Quebec Canada
- Axe Neurosciences, Centre de Recherche du CHU de Québec; Université Laval; Québec Canada
| | - Cyntia Tremblay
- Axe Neurosciences, Centre de Recherche du CHU de Québec; Université Laval; Québec Canada
| | - Isabelle St-Amour
- Axe Neurosciences, Centre de Recherche du CHU de Québec; Université Laval; Québec Canada
| | - Caroline Pierrisnard
- Faculté de Pharmacie; Université Laval; Quebec Canada
- Axe Neurosciences, Centre de Recherche du CHU de Québec; Université Laval; Québec Canada
| | - Audrey Faucher-Genest
- Axe Neurosciences, Centre de Recherche du CHU de Québec; Université Laval; Québec Canada
| | - Vincent Emond
- Axe Neurosciences, Centre de Recherche du CHU de Québec; Université Laval; Québec Canada
| | - Carl Julien
- Faculté de Pharmacie; Université Laval; Quebec Canada
- Axe Neurosciences, Centre de Recherche du CHU de Québec; Université Laval; Québec Canada
| | - Frédéric Calon
- Faculté de Pharmacie; Université Laval; Quebec Canada
- Axe Neurosciences, Centre de Recherche du CHU de Québec; Université Laval; Québec Canada
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Akiguchi I, Pallàs M, Budka H, Akiyama H, Ueno M, Han J, Yagi H, Nishikawa T, Chiba Y, Sugiyama H, Takahashi R, Unno K, Higuchi K, Hosokawa M. SAMP8 mice as a neuropathological model of accelerated brain aging and dementia: Toshio Takeda's legacy and future directions. Neuropathology 2017; 37:293-305. [PMID: 28261874 DOI: 10.1111/neup.12373] [Citation(s) in RCA: 128] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Revised: 01/23/2017] [Accepted: 01/24/2017] [Indexed: 12/14/2022]
Abstract
Senescence accelerated mice P8 (SAMP8) show significant age-related deteriorations in memory and learning ability in accordance with early onset and rapid advancement of senescence. Brains of SAMP8 mice reveal an age-associated increase of PAS-positive granular structures in the hippocampal formation and astrogliosis in the brain stem and hippocampus. A spongy degeneration in the brain stem appears at 1 month of age and reaches a maximum at 4-8 months. In addition, clusters of activated microglia also appear around the vacuoles in the brain stem. β/A4(Aβ) protein-like immunoreactive granular structures are observed in various regions and increase in number markedly with age. Other age-associated histological changes include cortical atrophy, neuronal cell loss in locus coeruleus and lateral tegmental nuclei, intraneuronal accumulation of lipopigments in Purkinje cells and eosinophilic inclusion bodies in thalamic neurons. A blood-brain barrier dysfunction and astrogliosis are also prominent with advancing age in the hippocampus. These changes are generally similar to the pathomorphology of aging human brains and characterized by their association with some specific glioneuronal reactions. As for the hallmarks of Alzheimer brains, tau morphology has not yet been confirmed regardless of the age-related increase in phosphorylated tau in SAMP8 mice brains, but early age-related Aβ deposition in the hippocampus has recently been published. SAMP8 mice are, therefore, not only a senescence-accelerated model but also a promising model for Alzheimer's disease and other cognitive disorders.
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Affiliation(s)
- Ichiro Akiguchi
- Center of Neurological and Cerebrovascular Diseases, Koseikai Takeda Hospital, Kyoto, Japan.,Department of Health Science, Kyoto Koka Women's University, Kyoto, Japan
| | - Mercè Pallàs
- Pharmacology Section and Institute of Neuroscience, University of Barcelona, Barcelona, Spain
| | - Herbert Budka
- Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland
| | - Haruhiko Akiyama
- Department of Clinical Research, Yokohama Brain and Spine Center, Yokohama, Japan
| | - Masaki Ueno
- Department of Pathology and Host Defence, Faculty of Medicine, Kagawa University, Takamatsu, Japan
| | - Jingxian Han
- The First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Hideo Yagi
- Center of Neurological and Cerebrovascular Diseases, Koseikai Takeda Hospital, Kyoto, Japan
| | - Tomohumi Nishikawa
- Department of Health Science, Kyoto Koka Women's University, Kyoto, Japan
| | - Yoichi Chiba
- Department of Pathology and Host Defence, Faculty of Medicine, Kagawa University, Takamatsu, Japan
| | | | - Ryoya Takahashi
- Department of Biochemistry, Faculty of Pharmaceutical Sciences, Toho University, Chiba, Japan
| | - Keiko Unno
- School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Keiichi Higuchi
- Department of Aging Biology, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Japan
| | - Masanori Hosokawa
- Institute for Developmental Research, Aichi Human Service Center, Nagoya, Japan
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Zhou W, Cheng X, Zhang Y. Effect of Liuwei Dihuang decoction, a traditional Chinese medicinal prescription, on the neuroendocrine immunomodulation network. Pharmacol Ther 2016; 162:170-8. [DOI: 10.1016/j.pharmthera.2016.02.004] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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Hippocampus-dependent spatial memory impairment due to molar tooth loss is ameliorated by an enriched environment. Arch Oral Biol 2015; 61:1-7. [PMID: 26476746 DOI: 10.1016/j.archoralbio.2015.10.006] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Revised: 09/11/2015] [Accepted: 10/05/2015] [Indexed: 11/20/2022]
Abstract
BACKGROUND AND OBJECTIVE Teeth are crucial, not only for mastication, but for overall nutrition and general health, including cognitive function. Aged mice with chronic stress due to tooth loss exhibit impaired hippocampus-dependent learning and memory. Exposure to an enriched environment restores the reduced hippocampal function. Here, we explored the effects of an enriched environment on learning deficits and hippocampal morphologic changes in aged senescence-accelerated mouse strain P8 (SAMP8) mice with tooth loss. DESIGN Eight-month-old male aged SAMP8 mice with molar intact or with molars removed were housed in either a standard environment or enriched environment for 3 weeks. The Morris water maze was performed for spatial memory test. The newborn cell proliferation, survival, and differentiation in the hippocampus were analyzed using 5-Bromodeoxyuridine (BrdU) immunohistochemical method. The hippocampal brain-derived neurotrophic factor (BDNF) levels were also measured. RESULTS Mice with upper molars removed (molarless) exhibited a significant decline in the proliferation and survival of newborn cells in the dentate gyrus (DG) as well as in hippocampal BDNF levels. In addition, neuronal differentiation of newly generated cells was suppressed and hippocampus-dependent spatial memory was impaired. Exposure of molarless mice to an enriched environment attenuated the reductions in the hippocampal BDNF levels and neuronal differentiation, and partially improved the proliferation and survival of newborn cells, as well as the spatial memory ability. CONCLUSION These findings indicated that an enriched environment could ameliorate the hippocampus-dependent spatial memory impairment induced by molar tooth loss.
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Bourdenx M, Dovero S, Engeln M, Bido S, Bastide MF, Dutheil N, Vollenweider I, Baud L, Piron C, Grouthier V, Boraud T, Porras G, Li Q, Baekelandt V, Scheller D, Michel A, Fernagut PO, Georges F, Courtine G, Bezard E, Dehay B. Lack of additive role of ageing in nigrostriatal neurodegeneration triggered by α-synuclein overexpression. Acta Neuropathol Commun 2015. [PMID: 26205255 PMCID: PMC4513748 DOI: 10.1186/s40478-015-0222-2] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
INTRODUCTION Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons as well as the presence of proteinaceous inclusions named Lewy bodies. α-synuclein (α-syn) is a major constituent of Lewy bodies, and the first disease-causing protein characterized in PD. Several α-syn-based animal models of PD have been developed to investigate the pathophysiology of PD, but none of them recapitulate the full picture of the disease. Ageing is the most compelling and major risk factor for developing PD but its impact on α-syn toxicity remains however unexplored. In this study, we developed and exploited a recombinant adeno-associated viral (AAV) vector of serotype 9 overexpressing mutated α-syn to elucidate the influence of ageing on the dynamics of PD-related neurodegeneration associated with α-syn pathology in different mammalian species. RESULTS Identical AAV pseudotype 2/9 vectors carrying the DNA for human mutant p.A53T α-syn were injected into the substantia nigra to induce neurodegeneration and synucleinopathy in mice, rats and monkeys. Rats were used first to validate the ability of this serotype to replicate α-syn pathology and second to investigate the relationship between the kinetics of α-syn-induced nigrostriatal degeneration and the progressive onset of motor dysfunctions, strikingly reminiscent of the impairments observed in PD patients. In mice, AAV2/9-hα-syn injection into the substantia nigra was associated with accumulation of α-syn and phosphorylated hα-syn, regardless of mouse strain. However, phenotypic mutants with either accelerated senescence or resistance to senescence did not display differential susceptibility to hα-syn overexpression. Of note, p-α-syn levels correlated with nigrostriatal degeneration in mice. In monkeys, hα-syn-induced degeneration of the nigrostriatal pathway was not affected by the age of the animals. Unlike mice, monkeys did not exhibit correlations between levels of phosphorylated α-syn and neurodegeneration. CONCLUSIONS In conclusion, AAV2/9-mediated hα-syn induces robust nigrostriatal neurodegeneration in mice, rats and monkeys, allowing translational comparisons among species. Ageing, however, neither exacerbated nigrostriatal neurodegeneration nor α-syn pathology per se. Our unprecedented multi-species investigation thus favours the multiple-hit hypothesis for PD wherein ageing would merely be an aggravating, additive, factor superimposed upon an independent disease process.
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Yan WW, Chen GH, Wang F, Tong JJ, Tao F. Long-term acarbose administration alleviating the impairment of spatial learning and memory in the SAMP8 mice was associated with alleviated reduction of insulin system and acetylated H4K8. Brain Res 2015; 1603:22-31. [PMID: 25645154 DOI: 10.1016/j.brainres.2015.01.042] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2014] [Revised: 01/20/2015] [Accepted: 01/23/2015] [Indexed: 12/14/2022]
Abstract
Age-associated memory impairment (AAMI) not only reduces the quality of life for the elderly but also increases the costs of healthcare for society. Methods that can regulate glucose metabolism, insulin/insulin-like growth factor 1 (IGF-1) system and acetylated histone H4 lysine 8 (H4K8ac), one of the most well-researched facets of histone acetylation modification associating with cognition, tend to ameliorate the AAMI. Here, we used SAMP8 mice, the excellent animal model of aging and AAMI, to study the effect of long-term treatment with acarbose, an inhibitor of a-glucosidase, on AAMI and explore whether blood glucose, insulin/IGF-1 system and H4K8ac are associated with potential effects. The treatment group received acarbose (20mg/kg/d, dissolved in drinking water) at the age of 3-month until 9-month old before the behavioral test, and the controls only received water. Compared to the young controls (3-month-old, n=11), the old group (9-month-old, n=8) had declined abilities of spatial learning and memory and levels of serum insulin, hippocampal insulin receptors (InsRs) and H4K8ac. Interestingly, the acarbose group (9-month-old, n=9) showed better abilities of spatial learning and memory and higher levels of insulin, InsRs and H4K8ac relative to the old controls. Good performance of spatial learning and memory was positively correlated with the elevated insulin, InsRs and H4K8ac. All these results suggested that long-term administration of acarbose could alleviate the age-related impairment of spatial learning and memory in the SAMP8 mice, and the alleviated reduction of an insulin system and H4K8ac might be associated with the alleviation.
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Affiliation(s)
- Wen-Wen Yan
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, PR China
| | - Gui-Hai Chen
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, PR China; Department of Neurology, The First People׳s Hospital of Chenzhou, Southern Medical University, Chenzhou 423000, Hunan Province, PR China.
| | - Fang Wang
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, PR China
| | - Jing-Jing Tong
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, PR China
| | - Fei Tao
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, PR China
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Tripchlorolide improves age-associated cognitive deficits by reversing hippocampal synaptic plasticity impairment and NMDA receptor dysfunction in SAMP8 mice. Behav Brain Res 2014; 258:8-18. [DOI: 10.1016/j.bbr.2013.10.010] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2013] [Revised: 09/29/2013] [Accepted: 10/03/2013] [Indexed: 02/02/2023]
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Cheng XR, Zhou WX, Zhang YX. The behavioral, pathological and therapeutic features of the senescence-accelerated mouse prone 8 strain as an Alzheimer's disease animal model. Ageing Res Rev 2014; 13:13-37. [PMID: 24269312 DOI: 10.1016/j.arr.2013.10.002] [Citation(s) in RCA: 104] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2013] [Revised: 10/10/2013] [Accepted: 10/30/2013] [Indexed: 12/22/2022]
Abstract
Alzheimer's disease (AD) is a widespread and devastating progressive neurodegenerative disease. Disease-modifying treatments remain beyond reach, and the etiology of the disease is uncertain. Animal model are essential for identifying disease mechanisms and developing effective therapeutic strategies. Research on AD is currently being carried out in rodent models. The most common transgenic mouse model mimics familial AD, which accounts for a small percentage of cases. The senescence-accelerated mouse prone 8 (SAMP8) strain is a spontaneous animal model of accelerated aging. Many studies indicate that SAMP8 mice harbor the behavioral and histopathological signatures of AD, namely AD-like cognitive and behavioral alterations, neuropathological phenotypes (neuron and dendrite spine loss, spongiosis, gliosis and cholinergic deficits in the forebrain), β-amyloid deposits resembling senile plaques, and aberrant hyperphosphorylation of Tau-like neurofibrillary tangles. SAMP8 mice are useful in the development of novel therapies, and many pharmacological agents and approaches are effective in SAMP8 mice. SAMP8 mice are considered a robust model for exploring the etiopathogenesis of sporadic AD and a plausible experimental model for developing preventative and therapeutic treatments for late-onset/age-related AD, which accounts for the vast majority of cases.
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Affiliation(s)
- Xiao-rui Cheng
- Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
| | - Wen-xia Zhou
- Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
| | - Yong-xiang Zhang
- Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
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Adler BL, Yarchoan M, Hwang HM, Louneva N, Blair JA, Palm R, Smith MA, Lee HG, Arnold SE, Casadesus G. Neuroprotective effects of the amylin analogue pramlintide on Alzheimer's disease pathogenesis and cognition. Neurobiol Aging 2013; 35:793-801. [PMID: 24239383 DOI: 10.1016/j.neurobiolaging.2013.10.076] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2013] [Revised: 10/05/2013] [Accepted: 10/06/2013] [Indexed: 12/24/2022]
Abstract
Amylin is a metabolic peptide hormone that is co-secreted with insulin from beta cells in the pancreas and activates many of the downstream targets of insulin. To investigate the relationship between this hormone and Alzheimer's disease (AD), we measured plasma human amylin levels in 206 subjects with AD, 64 subjects with mild cognitive impairment, and 111 subjects with no cognitive impairment and found significantly lower amylin levels among subjects with AD and mild cognitive impairment compared with the cognitively intact subjects. To investigate mechanisms underlying amylin's effects in the brain, we administered chronic infusions of the amylin analog pramlintide in the senescence-accelerated prone mouse, a mouse model of sporadic AD. Pramlintide administration improved performance in the novel object recognition task, a validated test of memory and cognition. The pramlintide-treated mice had increased expression of the synaptic marker synapsin I and the kinase cyclin-dependent kinase-5 in the hippocampus, as well as decreased oxidative stress and inflammatory markers in the hippocampus. A dose-dependent increase in cyclin-dependent kinase-5 and activation of extracellular-signal-regulated-kinases 1/2 by pramlintide treatment in vitro was also present indicating functionality of the amylin receptor in neurons. Together these results suggest that amylin analogs have neuroprotective properties and might be of therapeutic benefit in AD.
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Affiliation(s)
- Brittany L Adler
- Department of Neurosciences, Case Western Reserve University, Cleveland OH USA
| | - Mark Yarchoan
- Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
| | - Hae Min Hwang
- Department of Neurosciences, Case Western Reserve University, Cleveland OH USA
| | - Natalia Louneva
- Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
| | - Jeffrey A Blair
- Department of Neurosciences, Case Western Reserve University, Cleveland OH USA
| | - Russell Palm
- Department of Neurosciences, Case Western Reserve University, Cleveland OH USA
| | - Mark A Smith
- Department of Pathology, Case Western Reserve University, Cleveland OH USA
| | - Hyoung-Gon Lee
- Department of Pathology, Case Western Reserve University, Cleveland OH USA
| | - Steven E Arnold
- Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
| | - Gemma Casadesus
- Department of Neurosciences, Case Western Reserve University, Cleveland OH USA.
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Neuroprotective effects of forsythiaside on learning and memory deficits in senescence-accelerated mouse prone (SAMP8) mice. Pharmacol Biochem Behav 2013; 105:134-41. [PMID: 23290932 DOI: 10.1016/j.pbb.2012.12.016] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2011] [Revised: 11/25/2012] [Accepted: 12/19/2012] [Indexed: 11/20/2022]
Abstract
Forsythiaside (3,4-dihydroxy-β-phenethyl-O-α-L-rhamnopyranosyl-(1→6)-4-O-caffeo yl-β-d-glucopyranoside, C29H36O15), which is isolated from air-dried fruits of Forsythia suspensa, has been shown to possess anti-oxidant, anti-bacterial and anti-inflammatory activities. The aim of this study is to investigate the neuroprotective effects of forsythiaside on learning and memory deficits in the senescence-accelerated mouse prone 8 (SAMP8, a model of age-dependent neurodegenerative disorders such as Alzheimer's disease). Forsythiaside (60, 120 and 240mg/kg) was orally administered to aged (8months old) SAMP8 mice for 45days followed by evaluating cognitive impairment (Morris water maze and step-through passive avoidance), inflammation (interleukin-1β (IL-1β) and interleukin-6 (IL-6) levels), oxidative stress (glutathione peroxidase (GSH-Px) and total superoxide dismutase (T-SOD) activities; malondialdehyde (MDA) and nitric oxide (NO) contents) and neurotransmitter such as norepinephrine (NE), dopamine (DA), 5-hydroxytryptamine (5-HT), glutamate (GLU) gamma-aminobutyric acid (GABA) and acetyl choline (ACh). In Morris water maze, forsythiaside had significantly reduced the latency time, the crossing numbers and time spent in target quadrant compared to aged SAMP8 mice. In passive avoidance test, a significant decline in number of errors while increase in latency was observed when compared with aged SAMP8 mice. Furthermore, a significant decrease in IL-1β, NO, MDA and NE levels, and an increase in T-SOD and GSH-Px activities and GLU and Ach levels were evident in the brain homogenates of forsythiaside-treated mice compared to aged SAMP8 mice. These findings demonstrated that forsythiaside may be a useful treatment against amnesia.
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Pallàs M. Senescence-Accelerated Mice P8: A Tool to Study Brain Aging and Alzheimer's Disease in a Mouse Model. ACTA ACUST UNITED AC 2012. [DOI: 10.5402/2012/917167] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The causes of aging remain unknown, but they are probably intimately linked to a multifactorial process that affects cell networks to varying degrees. Although a growing number of aging and Alzheimer’s disease (AD) animal models are available, a more comprehensive and physiological mouse model is required. In this context, the senescence-accelerated mouse prone 8 (SAMP8) has a number of advantages, since its rapid physiological senescence means that it has about half the normal lifespan of a rodent. In addition, according to data gathered over the last five years, some of its behavioral traits and histopathology resemble AD human dementia. SAMP8 has remarkable pathological similarities to AD and may prove to be an excellent model for acquiring more in-depth knowledge of the age-related neurodegenerative processes behind brain senescence and AD in particular. We review these facts and particularly the data on parameters related to neurodegeneration. SAMP8 also shows signs of aging in the immune, vascular, and metabolic systems, among others.
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Affiliation(s)
- Mercè Pallàs
- Unitat de Farmacologia i Farmacognòosia, Facultat de Farmàcia, Institut de Biomedicina (IBUB), Universitat de Barcelona y Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Nucli Universitari de Pedralbes, 08028 Barcelona, Spain
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43
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Dobarro M, Orejana L, Aguirre N, Ramírez MJ. Propranolol restores cognitive deficits and improves amyloid and Tau pathologies in a senescence-accelerated mouse model. Neuropharmacology 2012; 64:137-44. [PMID: 22824191 DOI: 10.1016/j.neuropharm.2012.06.047] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2012] [Revised: 06/19/2012] [Accepted: 06/24/2012] [Indexed: 11/25/2022]
Abstract
Ageing is associated with a deterioration of cognitive performance and with increased risk of neurodegenerative disorders. Hypertension is the most-prevalent modifiable risk factor for cardiovascular morbidity and mortality worldwide, and clinical data suggest that hypertension is a risk factor for Alzheimer's disease (AD). In the present study we tested whether propranolol, a β-receptor antagonist commonly used as antihypertensive drug, could ameliorate the cognitive impairments and increases in AD-related markers shown by the senescence-accelerated mouse prone-8 (SAMP8). Propranolol administration (5 mg/kg for 3 weeks) to 6-month-old SAMP8 mice attenuated cognitive memory impairments shown by these mice in the novel object recognition test. In the hippocampus of SAMP8 mice it has been found increases in Aβ(42) levels, the principal constituent of amyloid plaques observed in AD, accompanied by both an increased expression of the cleaving enzyme BACE1 and a decreased expression of the degrading enzyme IDE. All these effects were reversed by propranolol treatment. Tau hyperphosphorylation (PHF-1 epitope) shown by SAMP8 mice at this age was also decreased in the hippocampus of propranolol-treated mice, an effect probably related to a decrease in JNK1 expression. Interestingly, propranolol also phosphorylated Akt in SAMP8 mice, which was associated with an increase of glycogen synthase kinase-3β phosphorylation, contributing therefore to the reductions in Tau hyperphosphorylation. Synaptic pathology in SAMP8 mice, as shown by decreases in synaptophysin and BDNF, was also counteracted by propranolol treatment. Overall, propranolol might be beneficial in age-related brain dysfunction and could be an emerging candidate for the treatment of other neurodegenerative diseases. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
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Affiliation(s)
- Marta Dobarro
- Department of Pharmacology, University of Navarra, C/ Irunlarrea 1, 31008 Pamplona, Spain
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Pennesi ME, Neuringer M, Courtney RJ. Animal models of age related macular degeneration. Mol Aspects Med 2012; 33:487-509. [PMID: 22705444 DOI: 10.1016/j.mam.2012.06.003] [Citation(s) in RCA: 299] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Age related macular degeneration (AMD) is the leading cause of vision loss of those over the age of 65 in the industrialized world. The prevalence and need to develop effective treatments for AMD has lead to the development of multiple animal models. AMD is a complex and heterogeneous disease that involves the interaction of both genetic and environmental factors with the unique anatomy of the human macula. Models in mice, rats, rabbits, pigs and non-human primates have recreated many of the histological features of AMD and provided much insight into the underlying pathological mechanisms of this disease. In spite of the large number of models developed, no one model yet recapitulates all of the features of human AMD. However, these models have helped reveal the roles of chronic oxidative damage, inflammation and immune dysregulation, and lipid metabolism in the development of AMD. Models for induced choroidal neovascularization have served as the backbone for testing new therapies. This article will review the diversity of animal models that exist for AMD as well as their strengths and limitations.
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Affiliation(s)
- Mark E Pennesi
- Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR 97239, USA.
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45
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Iinuma M, Yasui S, Oonishi M, Kurata C, Ichihashi Y, Tamura Y, Kubo KY. Relationship between light and dark period activity cycles and oral condition in senescence-accelerated mice. Okajimas Folia Anat Jpn 2011; 88:29-36. [PMID: 21882594 DOI: 10.2535/ofaj.88.29] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
We investigated the effect of tooth absence and masticatory abnormalities due to powdered food feeding starting during the juvenile period on light and dark period activity cycles in senescence-accelerated mice (SAMP1). SAMP1 were divided into 5 groups: Group 1, maxillo-mandibular molar tooth extraction; Group 2, maxillary molar tooth extraction; Group 3, mandibular molar tooth extraction; Group 4, powdered food; and Group 5, sham-operated control. Senescence was observed earliest in the powdered food group. Total 24-hour activity was higher in the control group than in the four other groups. In the powdered food group, the dark period activity decreased to less than 60% of the total activity in the 36th week. In the tooth extraction groups (Groups 1-3), dark period activity decreased to less than 60% of the total activity in the 40th week. The control group dark period activity remained above 60% for the entire experimental period. Thus, the distinction between the light and dark periods disappeared earlier in the four experimental groups compared with the control group. Significant correlations were noted among total activity, degree of senescence, and percent dark period activity in each experimental group. Functional masticatory insufficiency promoted dementia and behavioral abnormalities in SAMP1.
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Affiliation(s)
- Mitsuo Iinuma
- Department of Pediatric Dentistry, Asahi University School of Dentistry, 1851-1 Hozumi, Mizuho, Gifu, 501-0296, Japan.
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46
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Kuhla A, Blei T, Jaster R, Vollmar B. Aging is associated with a shift of fatty metabolism toward lipogenesis. J Gerontol A Biol Sci Med Sci 2011; 66:1192-200. [PMID: 21835806 DOI: 10.1093/gerona/glr124] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The incidence of nonalcoholic fatty liver disease is steadily increasing among the elderly population. Lipid metabolism is transcriptionally controlled by the nuclear receptors retinoid acid receptor alpha, liver-X-receptor alpha, and peroxisome proliferator-activated receptor alpha and their target genes ABCA1, sterol regulatory element-binding protein-1c, and fatty acid synthase. Using senescence-accelerated prone mice (SAMP8), we addressed the question as to whether age-related increase of oxidative stress affects nuclear receptor gene expression. In contrast to SAMR1 control mice, young SAMP8 mice exhibit hepatic steatosis with increased hepatic cholesterol content, plasma triglyceride, and aspartate aminotransferase levels. This is accompanied by an increase of liver-X-receptor alpha and retinoid acid receptor alpha expression, whereas peroxisome proliferator-activated receptor alpha expression is found diminished. SAMP8 mice further reveal a lower expression of ABCA1 as well as of sterol regulatory element-binding protein-1c and higher expression of fatty acid synthase. The dysbalance between the nuclear receptors and their target genes most probably mediates hepatic steatosis and underlines the pathological relevance of nuclear receptor shift toward lipogenesis in fat metabolism of the elderly patient.
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Affiliation(s)
- Angela Kuhla
- Institute for Experimental Surgery, University of Rostock, Schillingallee 69a, D-18057 Rostock, Germany
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Shin EJ, Jeong JH, Chung YH, Kim WK, Ko KH, Bach JH, Hong JS, Yoneda Y, Kim HC. Role of oxidative stress in epileptic seizures. Neurochem Int 2011; 59:122-37. [PMID: 21672578 PMCID: PMC3606551 DOI: 10.1016/j.neuint.2011.03.025] [Citation(s) in RCA: 307] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2010] [Revised: 03/27/2011] [Accepted: 03/28/2011] [Indexed: 11/16/2022]
Abstract
Oxidative stress resulting from excessive free-radical release is likely implicated in the initiation and progression of epilepsy. Therefore, antioxidant therapies aimed at reducing oxidative stress have received considerable attention in epilepsy treatment. However, much evidence suggests that oxidative stress does not always have the same pattern in all seizures models. Thus, this review provides an overview aimed at achieving a better understanding of this issue. We summarize work regarding seizure models (i.e., genetic rat models, kainic acid, pilocarpine, pentylenetetrazol, and trimethyltin), oxidative stress as an etiologic factor in epileptic seizures (i.e., impairment of antioxidant systems, mitochondrial dysfunction, involvement of redox-active metals, arachidonic acid pathway activation, and aging), and antioxidant strategies for seizure treatment. Combined, this review highlights pharmacological mechanisms associated with oxidative stress in epileptic seizures and the potential for neuroprotection in epilepsy that targets oxidative stress and is supported by effective antioxidant treatment.
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Affiliation(s)
- Eun-Joo Shin
- Neuropsychopharamcology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, South Korea
| | - Ji Hoon Jeong
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, South Korea
| | - Yoon Hee Chung
- Department of Anatomy, College of Medicine, Chung-Ang University, Seoul 156-756, South Korea
| | - Won-Ki Kim
- Department of Neuroscience, College of Medicine, Korea University, Seoul 136-705, South Korea
| | - Kwang-Ho Ko
- Pharmacology Laboratory, College of Pharmacy, Seoul National University, Seoul 143-701, South Korea
| | - Jae-Hyung Bach
- Neuropsychopharamcology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, South Korea
| | - Jau-Shyong Hong
- Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA
| | - Yukio Yoneda
- Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School of Natural Science and Technology, Kanazawa, Ishikawa 920-1192, Japan
| | - Hyoung-Chun Kim
- Neuropsychopharamcology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, South Korea
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48
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Age-related autophagy alterations in the brain of senescence accelerated mouse prone 8 (SAMP8) mice. Exp Gerontol 2011; 46:533-41. [DOI: 10.1016/j.exger.2011.02.006] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2010] [Revised: 02/09/2011] [Accepted: 02/09/2011] [Indexed: 12/19/2022]
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Akase T, Nagase T, Huang L, Ibuki A, Minematsu T, Nakagami G, Ohta Y, Shimada T, Aburada M, Sugama J, Sanada H. Aging-like skin changes induced by ultraviolet irradiation in an animal model of metabolic syndrome. Biol Res Nurs 2011; 14:180-7. [PMID: 21444332 DOI: 10.1177/1099800411401013] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Both physiological skin aging and pathologic photo-aging caused by ultraviolet (UV) irradiation are mediated by latent inflammation and oxidative stress. Although numerous animal skin-aging models have used UV irradiation, most require massive doses or long-term irradiation. To establish a more refined skin-aging model, we focused on an animal model of metabolic syndrome (MS) because MS involves damage to various organs via oxidative stress or inflammation, similar to the changes associated with aging. We hypothesized that MS skin might exhibit more aging-like changes after milder, shorter-term UV irradiation than would normal animal skin under similar conditions, thus providing a useful model for skin aging. The authors therefore examined the skin from Tsumura Suzuki obese diabetic (TSOD) mice (MS model) and control Tsumura Suzuki non-obese (TSNO) mice before and after UV irradiation. Skin from TSOD mice had a thinner epidermis and dermis, a thicker fatty layer, reduced density and convolution of the fragmented collagen fibers, and upregulated expression of tumor necrosis factor (TNF)-α, a dual marker for inflammation and aging, compared to the skin from TSNO mice. UV irradiation affected TSOD skin more severely than TSNO skin, resulting in various changes resembling those in aged human skin, including damage to the dermis and subcutaneous fatty tissue, infiltration of inflammatory cells, and further upregulation of TNF-α expression. These results suggest that UV-irradiated TSOD mice may provide a new model of skin aging and imply that skin from humans with MS is more susceptible to UV- or aging-related damage than normal human skin.
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Affiliation(s)
- Tomoko Akase
- Department of Gerontological Nursing/Wound Care Management, Division of Health Science and Nursing, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
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del Valle J, Duran-Vilaregut J, Manich G, Pallàs M, Camins A, Vilaplana J, Pelegrí C. Cerebral amyloid angiopathy, blood-brain barrier disruption and amyloid accumulation in SAMP8 mice. NEURODEGENER DIS 2011; 8:421-9. [PMID: 21411981 DOI: 10.1159/000324757] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2010] [Accepted: 02/01/2011] [Indexed: 01/09/2023] Open
Abstract
Cerebrovascular dysfunction and β-amyloid peptide deposition on the walls of cerebral blood vessels might be an early event in the development of Alzheimer's disease. Here we studied the time course of amyloid deposition in blood vessels and blood-brain barrier (BBB) disruption in the CA1 subzone of the hippocampus of SAMP8 mice and the association between these two variables. We also studied the association between the amyloid deposition in blood vessels and the recently described amyloid clusters in the parenchyma, as well as the association of these clusters with vessels in which the BBB is disrupted. SAMP8 mice showed greater amyloid deposition in blood vessels than age-matched ICR-CD1 control mice. Moreover, at 12 months of age the number of vessels with a disrupted BBB had increased in both strains, especially SAMP8 animals. At this age, all the vessels with amyloid deposition showed BBB disruption, but several capillaries with an altered BBB showed no amyloid on their walls. Moreover, amyloid clusters showed no spatial association with vessels with amyloid deposition, nor with vessels in which the BBB had been disrupted. Finally, we can conclude that vascular amyloid deposition seems to induce BBB alterations, but BBB disruption may also be due to other factors.
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Affiliation(s)
- Jaume del Valle
- Departament de Fisiologia, Facultat de Farmàcia, Barcelona, Spain
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