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Alzheimer’s disease (AD) is the most common neurodegenerative disorder and it is characterized by a progressive cognitive decline that correlates with the appearance of synaptic dysfunction and neuronal loss in specific brain areas. Typical lesions consist in amyloid-β (Aβ)-containing plaques and neurofibrillary tangles primarily composed of hyperphosphorylated tau. Aβ accumulation and oligomerization is believed to appear early in the disease and act as an upstream pathogenic event that drives tau pathology. While a small percentage of AD cases are due to inherited mutations in genes that participate in Aβ production, the majority of AD cases still lack a clear cause although aging is widely considered to be the major risk factor. Recent studies have suggested that AD is tightly correlated with the accumulation of cells that become senescent due to the progressive build-up of cellular insults during pathological aging. However, the identification of senescent cells in the brain and their implication in brain dysfunction and neurodegenerative pathologies still need to be further explored. As the gradual reduction in telomere length is known to play a central role in cellular senescence, our main objective in this study was to evaluate how brain senescence caused by telomere attrition interconnects with brain dysfunction and AD. For the first part of the project, we characterized brain senescence using a mouse model that is genetically deficient for the RNA component of the telomerase (Terc-/-). This model has no telomerase activity and exhibits important telomere attrition and noticeable premature aging after the third generation (G3 Terc-/-). Using brain samples and cell-type specific primary cultures (neurons, astrocytes), we demonstrated that telomerase attrition induces several known senescence markers. We then evaluated how senescence affects the onset and progression of AD by crossing the Terc-/- mice with the 5xFAD mouse model of AD and evaluating several Aβ-induced neuropathological features. Our results indicated that cell senescence modifies the progression of AD neuropathology. Specifically, we found that telomere-induced senescence causes a reduction in Aβ plaques at an age when amyloid pathology is extensive. However, at an earlier age, the same model shows an increase in intraneuronal Aβ accumulation in the subiculum and cortical layer V, the two earliest affected brain regions in 5xfad mice. Decreased neuronal densities were observed in these specific brain regions in our senescence model, suggesting that intraneuronal Aβ accumulation causes neurodegeneration, and that this phenomenon is accelerated by cellular senescence. Overall, we believe our data have important implications for AD research as they demonstrate the key role of cellular senescence and intraneuronal Aβ in AD pathophysiology. Potential modulators of these underlying processes might become promising therapeutic targets for the disease.
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Suelves Caballol, N., Saleki, S., Ibrahim, T., Decottignies, A., & Kienlen-Campard, P. (2022). The role of brain senescence and telomere attrition in the neuropathology of Alzheimer’s disease. 14th Meeting of the Belgian Society for Neuroscience, Brussels, Belgium. https://hdl.handle.net/2078.5/238434