Telomere-induced senescence increases aberrant intraneuronal amyloid-β accumulation by impairing autophagy in a mouse model of Alzheimer's disease

Suelves, N.; Saleki, S.; Ibrahim, T.; Palomares, D.; Vrancx, C.; Vadukul, D. M.; Papadopoulos, N.; Viceconte, N.; Claude, E.; Constantinescu, S. N.; Decottignies, A.; Kienlen-Campard, P.

doi:10.1101/2022.10.17.512098

bioRxiv · 10.1101/2022.10.17.512098

Telomere-induced senescence increases aberrant intraneuronal amyloid-β accumulation by impairing autophagy in a mouse model of Alzheimer's disease

Suelves, N.·Saleki, S.·Ibrahim, T.·Palomares, D.·Vrancx, C.·Vadukul, D. M.·Papadopoulos, N.·Viceconte, N.·Claude, E.·Constantinescu, S. N.·Decottignies, A.·Kienlen-Campard, P.

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Abstract

Aging is a well-known risk factor for Alzheimers disease (AD) and other neurodegenerative pathologies, but the molecular and cellular changes occurring in the aging brain are poorly understood. AD pathology seems to correlate with the appearance of cells that become senescent due to the progressive accumulation of cellular insults causing DNA damage. In this study, we investigated the role of cellular senescence on AD pathology by crossing an amyloid-{beta} (A{beta}) mouse model of AD (5xFAD) with a mouse model of senescence that is genetically deficient for the RNA component of the telomerase (Terc-/-). Our results show that accelerated senescence reduces amyloid plaque formation and A{beta} levels at an age when full-blown amyloid pathology is observed in 5xFAD mice. However, early and aberrant intraneuronal A{beta} accumulation is observed in the subiculum and cortical layer V of senescent mice. Selective neurodegeneration linked to telomere attrition and early intraneuronal A{beta} accumulation was observed in these particular regions. Finally, our results suggest that the effect of senescence on amyloid pathology might be mediated through an alteration in autophagy function. Altogether, these findings demonstrate the instrumental role of senescence in intraneuronal A{beta} accumulation associated to AD pathophysiology, and further support future approaches targeting these processes for therapeutic intervention.

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Suelves, N., Saleki, S., Ibrahim, T., Palomares, D., Vrancx, C., Vadukul, D. M., Papadopoulos, N., Viceconte, N., Claude, E., Constantinescu, S. N., Decottignies, A., Kienlen-Campard, P.. 2022-10-21. Telomere-induced senescence increases aberrant intraneuronal amyloid-β accumulation by impairing autophagy in a mouse model of Alzheimer's disease. https://doi.org/10.1101/2022.10.17.512098

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