RESUMO
Cellular senescence, which is characterized by an irreversible cell-cycle arrest1 accompanied by a distinctive secretory phenotype2, can be induced through various intracellular and extracellular factors. Senescent cells that express the cell cycle inhibitory protein p16INK4A have been found to actively drive naturally occurring age-related tissue deterioration3,4 and contribute to several diseases associated with ageing, including atherosclerosis5 and osteoarthritis6. Various markers of senescence have been observed in patients with neurodegenerative diseases7-9; however, a role for senescent cells in the aetiology of these pathologies is unknown. Here we show a causal link between the accumulation of senescent cells and cognition-associated neuronal loss. We found that the MAPTP301SPS19 mouse model of tau-dependent neurodegenerative disease10 accumulates p16INK4A-positive senescent astrocytes and microglia. Clearance of these cells as they arise using INK-ATTAC transgenic mice prevents gliosis, hyperphosphorylation of both soluble and insoluble tau leading to neurofibrillary tangle deposition, and degeneration of cortical and hippocampal neurons, thus preserving cognitive function. Pharmacological intervention with a first-generation senolytic modulates tau aggregation. Collectively, these results show that senescent cells have a role in the initiation and progression of tau-mediated disease, and suggest that targeting senescent cells may provide a therapeutic avenue for the treatment of these pathologies.
Assuntos
Senescência Celular , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Neuroglia/metabolismo , Neuroglia/patologia , Proteínas tau/metabolismo , Compostos de Anilina/farmacologia , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Senescência Celular/efeitos dos fármacos , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Feminino , Gliose/metabolismo , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Emaranhados Neurofibrilares/metabolismo , Fosforilação/efeitos dos fármacos , Solubilidade , Sulfonamidas/farmacologia , Transgenes , Proteínas tau/químicaRESUMO
Background: Caloric restriction (CR) has been recognized for its benefits in delaying age-related diseases and extending lifespan. While its effects on amyloid pathology in Alzheimer's disease (AD) mouse models are well-documented, its effects on tauopathy, another hallmark of AD, are less explored. Objective: To assess the impact of a short-term 30% CR regimen on age-dependent spatial learning deficits and pathological features in a tauopathy mouse model. Methods: We subjected male PS19 tau P301S (hereafter PS19) and age-matched wildtype mice from two age cohorts (4.5 and 7.5 months old) to a 6-week 30% CR regimen. Spatial learning performance was assessed using the Barnes Maze test. Tau pathology, neuroinflammation, hippocampal cell proliferation, and neurogenesis were evaluated in the older cohort by immunohistochemical staining and RT-qPCR. Results: CR mitigated age-dependent spatial learning deficits in PS19 mice but exhibited limited effects on tau pathology and the associated neuroinflammation. Additionally, we found a decrease in hippocampal cell proliferation, predominantly of Iba1+âcells. Conclusions: Our findings reinforce the cognitive benefits conferred by CR despite its limited modulation of disease pathology. Given the pivotal role of microglia in tau-driven pathology, the observed reduction in Iba1+âcells under CR suggests potential therapeutic implications, particularly if CR would be introduced early in disease progression.
Assuntos
Doença de Alzheimer , Tauopatias , Camundongos , Masculino , Humanos , Animais , Proteínas tau/genética , Proteínas tau/farmacologia , Aprendizagem Espacial , Camundongos Transgênicos , Restrição Calórica , Doenças Neuroinflamatórias , Doença de Alzheimer/patologia , Tauopatias/patologia , Aprendizagem em Labirinto , Modelos Animais de DoençasRESUMO
Senescence-associated ß-galactosidase (hereafter SA-ß-gal) staining has now been employed for more than 20 years to identify the presence of senescent cells (Dimri et al., Proc Natl Acad Sci U S A 92:9363-9367, 1995). These cells, characterized by a permanent cell-cycle arrest (Hayflick and Moorhead, Exp Cell Res 25:585-621, 1961) and the production of a distinct secretory phenotype of cytokines, chemokines, and proteases (Coppe et al., PLoS Biol 6:2853-2868, 2008), have received much attention in recent years for their impacts on diverse biological processes. Here we describe a method to identify and quantify the specific cells that become senescent in vivo using transmission electron microscopy after SA-ß-gal staining that can be used in countless scenarios.