TELOMERE-INDUCED BRAIN SENESCENCE LOWERS AMYLOID BURDEN IN HUMANIZED APP-SAA KNOCK-IN MICE WHILE PROMOTING TAU PATHOLOGY AND NEURODEGENERATION IN PS19 TAUOPATHY MICE

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and is characterized by progressive cognitive decline associated with synaptic dysfunction and neuronal loss in vulnerable brain regions. Typical lesions consist of amyloid-β (Aβ)-containing plaques and neurofibrillary tangles primarily composed of hyperphosphorylated tau. While a small fraction of AD cases are caused by inherited mutations affecting Aβ production, most have unknown causes. Aging is the strongest risk factor for AD, highlighting the importance of investigating how pathological aging processes, such as senescence, contribute to disease progression.
Since telomere attrition is a known driver of cellular senescence, we used telomerase-deficient mice (Terc-/-) as a model of pathological aging, in which we confirmed increased expression of classical senescence markers. To evaluate the effects of senescence on amyloid pathology, Terc-/- mice were crossed with humanized APP-SAA knock-in mice. Telomere-induced senescence reduced cortical Aβ plaque load without altering neuronal viability, and no evidence of intraneuronal Aβ was found. To examine the impact of senescence on tau pathology, Terc-/- mice were crossed with the PS19 tauopathy model. In contrast to the amyloid model, senescence markedly increased tau phosphorylation, truncation and aggregation. These changes were accompanied by enhanced astrocytic and microglial activation, as well as pronounced neuronal loss in vulnerable brain regions.
Overall, our findings identify brain senescence as a key modifier of AD progression that preferentially exacerbates tau pathology while exerting more limited effects on amyloid pathology. These results have important implications for the development and interpretation of senescence-targeted therapies in AD.