scholarly journals DNA damage in tissue-resident macrophages leads to age-related neurodegeneration

2021 ◽  
Author(s):  
George garinis ◽  
Katerina Gkirtzimanaki ◽  
Edisona Tsakani ◽  
Ermioni Arvanitaki ◽  
Electra Nenedaki ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Purkinje Cell ◽  
The Elderly ◽  
Type I ◽  
Age Related ◽  
Purkinje Cell Death ◽  
Repair Defect ◽  
The Brain

Abstract Neurodegenerative disorders are a growing challenge for the elderly yet their etiology remains elusive. Here, we show that persistent DNA damage in tissue-resident macrophages carrying an ERCC1-XPF DNA repair defect leads to cerebellar ataxia in mice. We find that cytoplasmic chromatin fragments accumulate in the brain microglia of progeroid and naturally aged mice stimulating a type-I Interferon (IFN-I) response and are then packaged in extracellular vesicles (EVs) leading to Purkinje cell death and neurodegeneration in Er1CX/− animals. To reduce neuroinflammation, we developed an EV-based strategy to deliver recombinant DNase I specifically in inflamed Er1CX/− microglia in vivo. Our approach rapidly removes dsDNAs from the cytoplasm of microglial cells and in secreted EVs; it alleviates the IFN-I response, decreases Purkinje cell death and delays the onset of neuronal decline in Er1CX/− animals. Thus, brain microglia causally contribute to neurodegeneration allowing for the development of promising therapeutic strategies against age-related neuroinflammation.

c-Jun N-Terminal Kinase (JNK) and p38 Play Different Roles in Age-Related Purkinje Cell Death in Murine Organotypic Culture

2010 ◽  
Vol 10 (2) ◽  
pp. 281-290 ◽  
Author(s):  
Mariaelena Repici ◽  
Rosine Wehrlé ◽  
Xanthi Antoniou ◽  
Tiziana Borsello ◽  
Isabelle Dusart
Keyword(s):  
Cell Death ◽  
Purkinje Cell ◽  
Organotypic Culture ◽  
Age Related ◽  
Purkinje Cell Death

scholarly journals Age-related Purkinje cell death is steroid dependent: RORα haplo-insufficiency impairs plasma and cerebellar steroids and Purkinje cell survival

AGE ◽  
2011 ◽  
Vol 33 (4) ◽  
pp. 565-578 ◽  
Author(s):  
Sonja Janmaat ◽  
Yvette Akwa ◽  
Mohamed Doulazmi ◽  
Joëlle Bakouche ◽  
Vanessa Gautheron ◽  
...  
Keyword(s):  
Cell Death ◽  
Purkinje Cell ◽  
Cell Survival ◽  
Steroid Dependent ◽  
Age Related ◽  
Purkinje Cell Death

Implication of Bcl-2 and Caspase-3 in age-related Purkinje cell death in murine organotypic culture: an in vitro model to study apoptosis

2000 ◽  
Vol 12 (8) ◽  
pp. 2935-2949 ◽  
Author(s):  
Abdel M. Ghoumari ◽  
Rosine Wehrlé ◽  
Ora Bernard ◽  
Constantino Sotelo ◽  
Isabelle Dusart
Keyword(s):  
Cell Death ◽  
Purkinje Cell ◽  
In Vitro Model ◽  
Caspase 3 ◽  
Organotypic Culture ◽  
Age Related ◽  
Purkinje Cell Death ◽  
Vitro Model

Oxidative Stress, Ocular Disease and Diabetes Retinopathy

2019 ◽  
Vol 24 (40) ◽  
pp. 4726-4741 ◽  
Author(s):  
Orathai Tangvarasittichai ◽  
Surapon Tangvarasittichai
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Cell Death ◽  
Protein Modification ◽  
Morphological Changes ◽  
Corneal Dystrophy ◽  
Age Related Macular Degeneration ◽  
Ocular Diseases ◽  
Retinal Light Damage ◽  
Age Related

Background: Oxidative stress is caused by free radicals or oxidant productions, including lipid peroxidation, protein modification, DNA damage and apoptosis or cell death and results in cellular degeneration and neurodegeneration from damage to macromolecules. Results: Accumulation of the DNA damage (8HOdG) products and the end products of LPO (including aldehyde, diene, triene conjugates and Schiff’s bases) were noted in the research studies. Significantly higher levels of these products in comparison with the controls were observed. Oxidative stress induced changes to ocular cells and tissues. Typical changes include ECM accumulation, cell dysfunction, cell death, advanced senescence, disarrangement or rearrangement of the cytoskeleton and released inflammatory cytokines. It is involved in ocular diseases, including keratoconus, Fuchs endothelial corneal dystrophy, and granular corneal dystrophy type 2, cataract, age-related macular degeneration, primary open-angle glaucoma, retinal light damage, and retinopathy of prematurity. These ocular diseases are the cause of irreversible blindness worldwide. Conclusions: Oxidative stress, inflammation and autophagy are implicated in biochemical and morphological changes in these ocular tissues. The development of therapy is a major target for the management care of these ocular diseases.

scholarly journals Age influences susceptibility of brain capillary endothelial cells to La Crosse virus infection and cell death

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Rahul Basu ◽  
Vinod Nair ◽  
Clayton W. Winkler ◽  
Tyson A. Woods ◽  
Iain D. C. Fraser ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Death ◽  
Virus Infection ◽  
La Crosse Virus ◽  
Brain Capillary ◽  
Adult Mice ◽  
Age Related ◽  
Capillary Endothelial Cells ◽  
The Brain

Abstract Background A key factor in the development of viral encephalitis is a virus crossing the blood-brain barrier (BBB). We have previously shown that age-related susceptibility of mice to the La Crosse virus (LACV), the leading cause of pediatric arbovirus encephalitis in the USA, was associated with the ability of the virus to cross the BBB. LACV infection in weanling mice (aged around 3 weeks) results in vascular leakage in the olfactory bulb/tract (OB/OT) region of the brain, which is not observed in adult mice aged > 6–8 weeks. Thus, we studied age-specific differences in the response of brain capillary endothelial cells (BCECs) to LACV infection. Methods To examine mechanisms of LACV-induced BBB breakdown and infection of the CNS, we analyzed BCECs directly isolated from weanling and adult mice as well as established a model where these cells were infected in vitro and cultured for a short period to determine susceptibility to virus infection and cell death. Additionally, we utilized correlative light electron microscopy (CLEM) to examine whether changes in cell morphology and function were also observed in BCECs in vivo. Results BCECs from weanling, but not adult mice, had detectable infection after several days in culture when taken ex vivo from infected mice suggesting that these cells could be infected in vitro. Further analysis of BCECs from uninfected mice, infected in vitro, showed that weanling BCECs were more susceptible to virus infection than adult BCECs, with higher levels of infected cells, released virus as well as cytopathic effects (CPE) and cell death. Although direct LACV infection is not detected in the weanling BCECs, CLEM analysis of brain tissue from weanling mice indicated that LACV infection induced significant cerebrovascular damage which allowed virus-sized particles to enter the brain parenchyma. Conclusions These findings indicate that BCECs isolated from adult and weanling mice have differential viral load, infectivity, and susceptibility to LACV. These age-related differences in susceptibility may strongly influence LACV-induced BBB leakage and neurovascular damage allowing virus invasion of the CNS and the development of neurological disease.

Proinflammatory phenotype of coronary arteries promotes endothelial apoptosis in aging

2004 ◽  
Vol 17 (1) ◽  
pp. 21-30 ◽  
Author(s):  
Anna Csiszar ◽  
Zoltan Ungvari ◽  
Akos Koller ◽  
John G. Edwards ◽  
Gabor Kaley
Keyword(s):  
Cell Death ◽  
Coronary Arteries ◽  
Caspase 3 ◽  
Apoptotic Cell ◽  
The Elderly ◽  
Apoptotic Cell Death ◽  
Caspase 9 ◽  
No Donor ◽  
Endothelial Apoptosis ◽  
Age Related

Previously we demonstrated that aging in coronary arteries is associated with proinflammatory phenotypic changes and decreased NO bioavailability, which, we hypothesized, promotes vascular disease by enhancing endothelial apoptosis. To test this hypothesis we characterized proapoptotic alterations in the phenotype of coronary arteries of aged (26 mo old) and young (3 mo old) F344 rats. DNA fragmentation analysis and TUNEL assay showed that in aged vessels there was an approximately fivefold increase in the number of apoptotic endothelial cells. In aged coronary arteries there was an increased expression of TNFα, TNFβ, and caspase 9 (microarray, real-time PCR), as well as increased caspase 9 and caspase 3 activity, whereas expression of TNFR1, TNFα-converting enzyme (TACE), Bcl-2, Bcl-X(L), Bid, Bax, caspase 8, and caspase 3 were unchanged. In vessel culture (18 h) incubation of aged coronary arteries with a TNF blocking antibody or the NO donor S-nitroso-penicillamine (SNAP) decreased apoptotic cell death. Incubation of young arteries with exogenous TNFα increased caspase 9 activity and elicited endothelial apoptosis, which was attenuated by SNAP. Inhibition of NO synthesis in cultured young coronary arteries also induced apoptotic cell death and potentiated the apoptotic effect of TNFα. Thus we propose that age-related upregulation of TNFα and caspase 9 and decreased bioavailability of NO promote endothelial apoptosis in coronary arteries that may lead to impaired endothelial function and ischemic heart disease in the elderly.

Metabolomic Alterations in the Blood and Brain in Association with Alzheimer’s Disease: Evidence from in vivo to Clinical Studies

2021 ◽  
pp. 1-28
Author(s):  
Sirawit Sriwichaiin ◽  
Nipon Chattipakorn ◽  
Siriporn C. Chattipakorn
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Studies ◽  
Elderly Population ◽  
The Elderly ◽  
Pathological Findings ◽  
Major Health Problem ◽  
Major Health ◽  
The Brain

Alzheimer’s disease (AD) has become a major health problem among the elderly population. Some evidence suggests that metabolic disturbance possibly plays a role in the pathophysiology of AD. Currently, the study of metabolomics has been used to explore changes in multiple metabolites in several diseases, including AD. Thus, the metabolomics research in AD might provide some information regarding metabolic dysregulations, and their possible associated pathophysiology. This review summarizes the information discovered regarding the metabolites in the brain and the blood from the metabolomics research of AD from both animal and clinical studies. Additionally, the correlation between the changes in metabolites and outcomes, such as pathological findings in the brain and cognitive impairment are discussed. We also deliberate on the findings of cohort studies, demonstrating the alterations in metabolites before changes of cognitive function. All of these findings can be used to inform the potential identity of specific metabolites as possible biomarkers for AD.

Cognition in Ageing

2018 ◽  
pp. 118-133 ◽  
Author(s):  
Susmita Halder ◽  
Akash Kumar Mahato
Keyword(s):  
Cognitive Functions ◽  
The Elderly ◽  
Daily Functioning ◽  
Cognitive Changes ◽  
Geriatric Population ◽  
Medical Issues ◽  
Age Related ◽  
Growing Age ◽  
The Common ◽  
The Brain

This chapter focuses on cognitive functions and impairment in the elderly; its implications in daily functioning with inputs on differences in the existing literature. The chapter further focuses on the diagnostic and assessment issues and intervention strategies. Ageing is an inevitable phase of life and encompasses changes in physical, psychological and social realms of an individual. Concern with the dwindling health and presence of any medical issues make the geriatric population prone to develop mental health conditions. Poor memory and reduced functional ability is one of the common complaints from older adults coming to psychiatric or neurology clinics. Cognitive functions have been well documented regarding their role in daily functioning of an individual. With growing age of the brain; while some cognitive functions do slow down; some of the functions do evolve better with experience. In this context, it is important to differentiate between normal age related cognitive changes and symptoms of any degenerative disease.

Ageing and the human brain

2020 ◽  
pp. 170-182
Author(s):  
Verena Heise ◽  
Enikő Zsoldos ◽  
Klaus P. Ebmeier
Keyword(s):  
In Vivo Imaging ◽  
Allostatic Load ◽  
Public Health Medicine ◽  
Causal Factors ◽  
Stress Markers ◽  
Age Related ◽  
Brain Changes ◽  
Heuristic Device ◽  
The Brain

There is little doubt that the brain changes with time, and all research in psychiatry is predicated on holding age constant in comparing groups of patients or estimating the effect sizes of causal factors. Nevertheless, relatively little is known about the mechanisms that are responsible for translating time into ageing. This chapter tries, after an overview of the principal mechanisms involved in biological ageing, to summarize the age-related changes observable in brains in vivo and to demonstrate the types of investigations that may cast light on such mechanisms in the future. A useful heuristic device to order the multiple potential causes of ageing is the chronic stress–allostatic load model, widely employed in epidemiology, public health medicine, and health psychology. In vivo imaging provides a method to test the translation of intermediate stress markers, such as vascular risk, metabolic syndrome, or allostatic load, into predictors of age-related brain changes.

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