Elucidating the Role of Brain Senescence and Telomere Attrition in Alzheimer’s Disease Tauopathy

Abstract

AbstractBackgroundNeurodegenerative diseases are the most common age‐related pathologies, including Alzheimer’s disease (AD). Recent studies suggest that telomere attrition, the main trigger of cellular senescence, might contribute to brain dysfunction and neurodegeneration with age (Forero et al., 2016). Senescent brain cells have been found in AD patients (Musi et al., 2018), and studies in a transgenic mouse model of tauopathy have shown that the elimination of senescent cells led to an improvement in tau‐related neurodegeneration and cognitive decline (Bussian et al., 2018). However, little is known about the exact connection between senescent brain cells and neurodegenerative disorders on a cellular and molecular level. Here, we studied how brain senescence relates to the onset and progression of AD‐related tau pathology.MethodWe used a mouse model of senescence (TercKO), which is deficient for the RNA component of the telomerase, and presents telomere attrition and premature ageing with increasing generations (Blasco et al., 1997). We crossed it with the tauopathy mouse model Tau P301S (PS19), which carries the P301S mutant form of the human microtubule‐associated protein tau gene (MAPT), exhibiting tau pathology features observed in AD (Yoshiyama et al., 2007). By taking advantage of primary cultures, brain sections and brain extracts, and using biochemistry and molecular biology techniques, we examined the expression of tau neuropathological features in a senescent context. Furthermore, we evaluated the changes in classical and novel markers of senescence in a neurodegenerative context.ResultWe observed that telomere attrition induces several known senescence markers (i.e., senescence‐associated beta‐galactosidase or SA‐β‐gal activity, upregulation of interleukins IL‐1β and IL‐6, and cell cycle regulator p16) and this exacerbates tau phosphorylation in primary neurons and hippocampal tissue. Additionally, our results suggest that the senescent context might enhance tau‐induced neurodegeneration.ConclusionOur work indicates that senescence might be an upstream regulator of tau pathology, aggravating it and triggering tau‐related neurodegeneration. Our results further suggest that TercKO mice could be a useful animal model to study the pathological role of age‐associated brain senescence. Elucidating this process in more detail could lead to the identification of suitable intervention targets for AD treatment.