Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology

Abstract

Aging is the main risk factor for Alzheimer’s disease (AD) and other neurodegenerative pathologies, but the molecular and cellular changes underlying pathological aging of the nervous system 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. Senescence has also been shown to reduce the autophagic flux, a mechanism involved in clearing damaged proteins from the cell, and such impairment has been linked to AD pathogenesis. In this study, we investigated the role of cellular senescence on AD pathology by crossing a mouse model of AD-like amyloid-β (Aβ) pathology (5xFAD) with a mouse model of senescence that is genetically deficient for the RNA component of the telomerase (Terc−/−). We studied changes in amyloid pathology, neurodegeneration, and the autophagy process in brain tissue samples and primary cultures derived from these mice by complementary biochemical and immunostaining approaches. Postmortem human brain samples were also processed to evaluate autophagy defects in AD patients. Our results show that accelerated senescence produces an early accumulation of intraneuronal Aβ in the subiculum and cortical layer V of 5xFAD mice. This correlates with a reduction in amyloid plaques and Aβ levels in connecting brain regions at a later disease stage. Neuronal loss was specifically observed in brain regions presenting intraneuronal Aβ and was linked to telomere attrition. Our results indicate that senescence affects intraneuronal Aβ accumulation by impairing autophagy function and that early autophagy defects can be found in the brains of AD patients. Together, these findings demonstrate the instrumental role of senescence in intraneuronal Aβ accumulation, which represents a key event in AD pathophysiology, and emphasize the correlation between the initial stages of amyloid pathology and defects in the autophagy flux.

Intra-cellular accumulation of amyloid is a marker of selective neuronal vulnerability in Alzheimer’s disease

“…Our transcriptomic analysis suggests one such pathological mechanism may be impairment of autophagy-lysosomal activity in vulnerable neurons which may lead to intraAβ accumulation, as previously observed in AD mouse models 19,20 . Changes in the autophagy lysosomal pathway specific to AT8 + neurons have been observed before in patients affected by AD 47 and tauopathies 66 , showing however an increase in p62/SQSTM1 and LC3 expression, respectively.…”

“…To explore the relative expression of genes of the autophagy-lysosomal pathway previously associated with AD pathology including intraAβ accumulation in amyloid mouse models 19,20 , we tested for differential expression of genes involved in autophagy 55 and neurodegenerative diseases (AD and FTD; Table 6) 56 . We found that majority of genes tested were downregulated relatively specifically in the Exc−L5−RORB−LINC01202 cluster (Fig.…”

“…Recent work suggests intraAβ accumulation can arise with impairments of neuronal autophagy-lysosomal pathway 19,20 . GWAS studies have implicated these pathways in susceptibility to AD 21 , suggesting that they play roles early, before neuronal loss 22,23 .…”

“…Intraneuronal Aβ-42 (intraAβ) was found to accumulate in reelin + vulnerable neurons of the EC in both rats and humans 18 . Recent work suggests intraAβ accumulation can arise with impairments of neuronal autophagy–lysosomal pathway 19,20 . GWAS studies have implicated these pathways in susceptibility to AD 21 , suggesting that they play roles early, before neuronal loss 22,23 .…”

Redox changes and cellular senescence in Alzheimer's disease

“…Studies employing a mouse model of AD (APP/PS1) suggested a link between oxidative stress and cellular senescence, wherein, mice exposed to prolonged oxidative stress exhibited cellular alterations that closely resembled those observed in various senescent states like elevated expression of SA-β-gal, cell cycle arrest, and changes in the shape and structure of cells [ 45 , 46 ]. Zhang et al demonstrated the upregulation of ROS production and p53 expression in a human astrocyte cell line (U87) upon exposure to Aβ1-40, and this effect was reversed by galantamine pretreatment [ 47 ].…”