Aging and Disease最新文献

{"title":"Ovariectomy and High Fat-Sugar-Salt Diet Induced Alzheimer's Disease/Vascular Dementia Features in Mice.","authors":"Sahar Sweetat, Moti Ben Shabat, Paschalis Theotokis, Nir Suissa, Eleni Karafoulidou, Olga Touloumi, Rami Abu-Fanne, Oded Abramsky, Gilly Wolf, Ann Saada, Amit Lotan, Nikolaos Grigoriadis, Hanna Rosenmann","doi":"10.14336/AD.2024.03110","DOIUrl":"10.14336/AD.2024.03110","url":null,"abstract":"<p><p>While the vast majority of Alzheimer's disease (AD) is non-familial, the animal models of AD that are commonly used for studying disease pathogenesis and development of therapy are mostly of a familial form. We aimed to generate a model reminiscent of the etiologies related to the common late-onset Alzheimer's disease (LOAD) sporadic disease that will recapitulate AD/dementia features. Naïve female mice underwent ovariectomy (OVX) to accelerate aging/menopause and were fed a high fat-sugar-salt diet to expose them to factors associated with increased risk of development of dementia/AD. The OVX mice fed a high fat-sugar-salt diet responded by dysregulation of glucose/insulin, lipid, and liver function homeostasis and increased body weight with slightly increased blood pressure. These mice developed AD-brain pathology (amyloid and tangle pathologies), gliosis (increased burden of astrocytes and activated microglia), impaied blood vessel density and neoangiogenesis, with cognitive impairment. Thus, OVX mice fed on a high fat-sugar-salt diet imitate a non-familial sporadic/environmental form of AD/dementia with vascular damage. This model is reminiscent of the etiologies related to the LOAD sporadic disease that represents a high portion of AD patients, with an added value of presenting concomitantly AD and vascular pathology, which is a common condition in dementia. Our model can, thereby, provide a valuable tool for studying disease pathogenesis and for the development of therapeutic approaches.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":null,"pages":null},"PeriodicalIF":7.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11346392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141441975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glaucoma, More than Meets the Eye: Patterns of Demyelination Revealed in Human Postmortem Glaucomatous Optic Nerve.","authors":"Gabriella E Parrilla, Akanksha Salkar, Roshana Vander Wall, Vivek Gupta, Stuart L Graham, Yuyi You","doi":"10.14336/AD.2024.0336-1","DOIUrl":"10.14336/AD.2024.0336-1","url":null,"abstract":"<p><p>Glaucoma is a neurodegenerative disease affecting millions worldwide, characterised by retinal ganglion cell (RGC) degeneration which leads to blindness in more advanced cases. Although the pathogenesis and underlying mechanisms of glaucoma are not fully understood, there are theories that hint at demyelination playing a role in the disease process. Demyelination, or the degeneration of the myelin sheath surrounding axons, has been found in previous studies using animal models of glaucoma and clinical assessments of glaucoma patients. However, this has not been fully realised or quantified in glaucoma patients. Utilising postmortem optic nerve samples from glaucoma and healthy subjects, various immunohistochemical and morphological assessments were performed to determine the extent, if any, of demyelination in glaucomatous optic nerves. Our findings revealed that alongside nerve shrinkage and degeneration of nerve tissue fascicles, there were significantly less myelin proteins, specifically myelin basic protein (MBP), in glaucoma optic nerves. Additionally, the loss of MBP was correlated with decreased oligodendrocyte (OLG) precursors and increasing glial activity. This further supports previous evidence that demyelination may be a secondary degenerative process associated with glaucoma disease progression. Not only do these results provide evidence for potential disease mechanisms, but this is also the first study to quantify optic nerve demyelination in glaucoma postmortem tissue.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":null,"pages":null},"PeriodicalIF":7.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11346397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coupling of Alzheimer's Disease Genetic Risk Factors with Viral Susceptibility and Inflammation.","authors":"Can Cao, Gaoshuang Fu, Ruodan Xu, Ning Li","doi":"10.14336/AD.2023.1017","DOIUrl":"10.14336/AD.2023.1017","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a neurodegenerative disease characterized by persistent cognitive decline. Amyloid plaque deposition and neurofibrillary tangles are the main pathological features of AD brain, though mechanisms leading to the formation of lesions remain to be understood. Genetic efforts through genome-wide association studies (GWAS) have identified dozens of risk genes influencing the pathogenesis and progression of AD, some of which have been revealed in close association with increased viral susceptibilities and abnormal inflammatory responses in AD patients. In the present study, we try to present a list of AD candidate genes that have been shown to affect viral infection and inflammatory responses. Understanding of how AD susceptibility genes interact with the viral life cycle and potential inflammatory pathways would provide possible therapeutic targets for both AD and infectious diseases.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":null,"pages":null},"PeriodicalIF":7.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11346407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92152243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polypharmacological Potential of Phosphodiesterase 5 Inhibitors for the Treatment of Neurocognitive Disorders.","authors":"Ashish Kumar, Fred Kim, Dong-Keun Song, Jai Jun Choung","doi":"10.14336/AD.2023.1129","DOIUrl":"10.14336/AD.2023.1129","url":null,"abstract":"<p><p>The prevalence of neurocognitive disorders (NCD) increases every year as the population continues to age, leading to significant global health concerns. Overcoming this challenge requires identifying biomarkers, risk factors, and effective therapeutic interventions that might provide meaningful clinical benefits. For Alzheimer's disease (AD), one of the most studied NCD, approved drugs include acetylcholinesterase inhibitors (rivastigmine, donepezil, and galantamine), an NMDA receptor antagonist (memantine), and anti-amyloid monoclonal antibodies (aducanumab and lecanemab). These drugs offer limited relief, targeting singular pathological processes of the AD. Given the multifactorial nature of the NCDs, a poly-pharmacological strategy may lead to improved outcomes compared to the current standard of care. In this regard, phosphodiesterase 5 (PDE5) inhibitors emerged as promising drug candidates for the treatment of neurocognitive disorders. These inhibitors increase cGMP levels and CREB signaling, thus enhancing learning, memory and neuroprotection, while reducing Aβ deposition, tau phosphorylation, oxidative stress, and neuroinflammation. In the present article, we evaluate the therapeutic potential of different PDE5 inhibitors to outline their multifaceted impact in the NCDs.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":null,"pages":null},"PeriodicalIF":7.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11346399/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139545361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ocular delivery of Pigment Epithelium-Derived Factor (PEDF) as a neuroprotectant for Geographic Atrophy.","authors":"Emily F Warner, Laura Vaux, Kara Boyd, Peter S Widdowson, Katie M Binley, Andrew Osborne","doi":"10.14336/AD.2024.0216-1","DOIUrl":"10.14336/AD.2024.0216-1","url":null,"abstract":"<p><p>Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD), that starts with atrophic lesions in the outer retina that expand to cover the macula and fovea, leading to severe vision loss over time. Pigment Epithelium-Derived Factor (PEDF) has a diverse-range of properties, including its ability to promote cell survival, reduce inflammation, inhibit angiogenesis, combat oxidative stress, regulate autophagy, and stimulate anti-apoptotic pathways, making it a promising therapeutic candidate for GA. However, the relatively short half-life of PEDF protein has precluded its potential as a clinical therapy for GA since it would require frequent injections. Therefore, we describe administration of a PEDF gene, comparing and contrasting delivery routes, viral and non-viral vectors, and consider the critical challenges for PEDF as a neuroprotectant for GA.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":null,"pages":null},"PeriodicalIF":7.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11346394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139995149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glial Cell Activation and Immune Responses in Glaucoma: A Systematic Review of Human Postmortem Studies of the Retina and Optic Nerve.","authors":"Akanksha Salkar, Roshana Vander Wall, Devaraj Basavarajappa, Nitin Chitranshi, Gabriella E Parilla, Mehdi Mirzaei, Peng Yan, Stuart Graham, Yuyi You","doi":"10.14336/AD.2024.0103","DOIUrl":"10.14336/AD.2024.0103","url":null,"abstract":"<p><p>Although researched extensively the understanding regarding mechanisms underlying glaucoma pathogenesis remains limited. Further, the exact mechanism behind neuronal death remains elusive. The role of neuroinflammation in retinal ganglion cell (RGC) death has been prominently theorised. This review provides a comprehensive summary of neuroinflammatory responses in glaucoma. A systematic search of Medline and Embase for articles published up to 8th March 2023 yielded 32 studies using post-mortem tissues from glaucoma patients. The raw data were extracted from tables and text to calculate the standardized mean differences (SMDs). These studies utilized post-mortem tissues from glaucoma patients, totalling 490 samples, compared with 380 control samples. Among the included studies, 27 reported glial cell activation based on changes to cellular morphology and molecular staining. Molecular changes were predominantly attributed to astrocytes (62.5%) and microglia (15.6%), with some involvement of Muller cells. These glial cell changes included amoeboid microglial cells with increased CD45 or HLA-DR intensity and hypertrophied astrocytes with increased glial fibrillary acidic protein labelling. Further, changes to extracellular matrix proteins like collagen, galectin, and tenascin-C suggested glial cells' influence on structural changes in the optic nerve head. The activation of DAMPs-driven immune response and the classical complement cascade was reported and found to be associated with activated glial cells in glaucomatous tissue. Increased pro-inflammatory markers such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were also linked to glial cells. Glial cell activation was also associated with mitochondrial, vascular, metabolic and antioxidant component disruptions. Association of the activated glial cells with pro-inflammatory responses, dysregulation of homeostatic components and antigen presentation indicates that glial cell responses influence glaucoma progression. However, the exact mechanism triggering these responses and underlying interactions remains unexplored. This necessitates further research using human samples for an increased understanding of the precise role of neuroinflammation in glaucoma progression.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":null,"pages":null},"PeriodicalIF":7.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11346413/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140178991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From Insight to Eyesight: Unveiling the Secrets of the Insulin-Like Growth Factor Axis in Retinal Health.","authors":"Raju V S Rajala, Ammaji Rajala","doi":"10.14336/AD.2024.0128","DOIUrl":"10.14336/AD.2024.0128","url":null,"abstract":"<p><p>Insulin-like growth factor-1 (IGF-1) plays a diverse role in the retina, exerting its effects in both normal and diseased conditions. Deficiency of IGF-1 in humans leads to issues such as microcephaly, mental retardation, deafness, and postnatal growth failure. IGF-1 is produced in the retinal pigment epithelium (RPE) and activates the IGF-1 receptor (IGF-1R) in photoreceptor cells. When IGF-1R is absent in rod cells, it results in the degeneration of photoreceptors, emphasizing the neuroprotective function of IGF signaling in these cells. Contrastingly, in neovascular age-related macular degeneration (AMD), there is an overexpression of both IGF-1 and IGF-1R in RPE. The mechanisms behind this altered regulation of IGF-1 in diseased states are currently unknown. This comprehensive review provides recent insights into the role of IGF-1 in the health and disease of the retina, raising several unanswered questions that still need further investigation.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":null,"pages":null},"PeriodicalIF":7.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11346401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139650058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tryptophan Metabolism in Alzheimer's Disease with the Involvement of Microglia and Astrocyte Crosstalk and Gut-Brain Axis.","authors":"Lushuang Xie, Qiaofeng Wu, Kelin Li, Mohammed A S Khan, Andrew Zhang, Bharati Sinha, Sihui Li, Sulie L Chang, David L Brody, Mark W Grinstaff, Shuanhu Zhou, Gil Alterovitz, Pinghua Liu, Xin Wang","doi":"10.14336/AD.2024.0134","DOIUrl":"10.14336/AD.2024.0134","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is an age-dependent neurodegenerative disease characterized by extracellular Amyloid Aβ peptide (Aβ) deposition and intracellular Tau protein aggregation. Glia, especially microglia and astrocytes are core participants during the progression of AD and these cells are the mediators of Aβ clearance and degradation. The microbiota-gut-brain axis (MGBA) is a complex interactive network between the gut and brain involved in neurodegeneration. MGBA affects the function of glia in the central nervous system (CNS), and microbial metabolites regulate the communication between astrocytes and microglia; however, whether such communication is part of AD pathophysiology remains unknown. One of the potential links in bilateral gut-brain communication is tryptophan (Trp) metabolism. The microbiota-originated Trp and its metabolites enter the CNS to control microglial activation, and the activated microglia subsequently affect astrocyte functions. The present review highlights the role of MGBA in AD pathology, especially the roles of Trp per se and its metabolism as a part of the gut microbiota and brain communications. We (i) discuss the roles of Trp derivatives in microglia-astrocyte crosstalk from a bioinformatics perspective, (ii) describe the role of glia polarization in the microglia-astrocyte crosstalk and AD pathology, and (iii) summarize the potential of Trp metabolism as a therapeutic target. Finally, we review the role of Trp in AD from the perspective of the gut-brain axis and microglia, as well as astrocyte crosstalk, to inspire the discovery of novel AD therapeutics.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":null,"pages":null},"PeriodicalIF":7.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11346405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141445206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physical Exercise Counteracts Aging-Associated White Matter Demyelination Causing Cognitive Decline.","authors":"Tanya H Butt, Makoto Tobiume, Diane B Re, Shingo Kariya","doi":"10.14336/AD.2024.0216","DOIUrl":"10.14336/AD.2024.0216","url":null,"abstract":"<p><p>In the central nervous system, oligodendrocytes wrap around neuronal axons to form myelin, an insulating layer or sheath that allows for the efficient conductance of action potentials. In addition to structural insulation, myelin provides encased axons with nutrient, metabolic and defensive support. Demyelination, or myelin loss, can therefore cause axonal dysfunction, leading to neurological impairment and disease. In Alzheimer's disease (AD), progressive white matter demyelination is acknowledged as one of the earliest pathologies preceding symptom onset. Unfortunately, current pharmacotherapy for slowing demyelination or promoting remyelination in AD is nonexistent. Exercise is recognized for its wide-ranging benefits to human health, including improved mental health and the prevention of lifestyle-related diseases. Mounting evidence suggests the contribution of physical activity in delaying the progression of dementia in elderly populations. Recent mechanistic studies have shown that exercise facilitates myelination in the brain through the vitalization of intrinsic pro-myelination cues, such as increased neurotrophic factors and electrical activity. In this review, we summarize and discuss the potential of physical exercise on counteracting aging-associated white matter demyelination, which causes cognitive decline in AD. We highlight the need of further basic and clinical research investigations on this topic to establish novel approaches for healthy and improved brain aging.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":null,"pages":null},"PeriodicalIF":7.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11346408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139911827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain-Derived Neurotrophic Factor Val66Met is Associated with Variation in Cortical Structure in Healthy Aging Subjects.","authors":"Ting Shen, Samran Sheriff, Yuyi You, Jiyang Jiang, Angela Schulz, Heather Francis, Mehdi Mirzaei, Danit Saks, Viswanthram Palanivel, Devaraj Basavarajappa, Nitin Chitranshi, Veer Gupta, Wei Wen, Perminder S Sachdev, Huixun Jia, Xiaodong Sun, Stuart L Graham, Vivek K Gupta","doi":"10.14336/AD.2024.0346","DOIUrl":"10.14336/AD.2024.0346","url":null,"abstract":"<p><p>Aging is associated with progressive brain atrophy and declines in learning and memory, often attributed to hippocampal or cortical deterioration. The role of brain-derived neurotrophic factor (BDNF) in modulating the structural and functional changes in the brain and visual system, particularly in relation to BDNF Val66Met polymorphism, remains underexplored. In this present cross-sectional observational study, we aimed to assess the effects of BDNF polymorphism on brain structural integrity, cognitive function, and visual pathway alterations. A total of 108 older individuals with no evidence of dementia and a mean (SD) age of 67.3 (9.1) years were recruited from the Optic Nerve Decline and Cognitive Change (ONDCC) study cohort. The BDNF Met allele carriage had a significant association with lower entorhinal cortex volume (6.7% lower compared to the Val/Val genotype, P = 0.02) and posterior cingulate volume (3.2% lower than the Val/Val group, P = 0.03), after adjusting for confounding factors including age, sex and estimated total intracranial volumes (eTIV). No significant associations were identified between the BDNF Val66Met genotype and other brain volumetric or diffusion measures, cognitive performances, or vision parameters except for temporal retinal nerve fibre layer thickness. Small but significant correlations were found between visual structural and functional, cognitive, and brain morphological metrics. Our findings suggest that carriage of BDNF Val66Met polymorphism is associated with lower entorhinal cortex and posterior cingulate volumes and may be involved in modulating the cortical morphology along the aging process.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":null,"pages":null},"PeriodicalIF":7.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11346411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141445198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}