Impaired Autophagy in APOE4 Astrocytes

Abstract

Alzheimer's disease (AD) is the most prevalent form of dementia in elderly. Genetic studies revealed allelic segregation of the apolipoprotein E (ApoE) gene in sporadic AD and in families with higher risk of AD. The mechanisms underlying the pathological effects of ApoE4 are not yet entirely clear. Several studies indicate that autophagy, which plays an important role in degradation pathways of proteins, organelles and protein aggregates, may be impaired in AD. In the present study, we investigated the effects of ApoE4 versus the ApoE3 isoform on the process of autophagy in mouse-derived astrocytes. The results obtained reveal that under several autophagy-inducing conditions, astrocytes expressing ApoE4 exhibit lower autophagic flux compared to astrocytes expressing ApoE3. Using an in situ model, we examined the role of autophagy and the effects thereon of ApoE4 in the elimination of Aβ plaques from isolated brain sections of transgenic 5xFAD mice. This revealed that ApoE4 astrocytes eliminate Aβ plaques less effectively than the corresponding ApoE3 astrocytes. Additional experiments showed that the autophagy inducer, rapamycin, enhances Aβ plaque degradation by ApoE4 astrocytes whereas the autophagy inhibitor, chloroquine, blocks Aβ plaque degradation by ApoE3 astrocytes. Taken together, these findings show that ApoE4 impairs autophagy in astrocyte cultures and that this effect is associated with reduced capacity to clear Aβ plaques. This suggests that impaired autophagy may play a role in mediating the pathological effects of ApoE4 in AD.

ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy

“…3b, c), suggesting ApoE4 may affect autophagy-mediated tau clearance. This is consistent with a previous report of impaired autophagy associated with ApoE4 14 . ApoE levels in the TE mice followed the pattern E2>E3>E4 (Extended Data Fig.…”

Autophagy induction in the treatment of Alzheimer's disease

“…As for rapamycin, its beneficial effects on Aβ/tau pathology and cognitive impairments occurs in parallel with induction of autophagosome formation and increased autophagic degradation in transgenic mice models, implying a possible link between these observation (Pierzynowska et al, 2018). Moreover, studies conducted in cellular models of AD have demonstrated that autophagy inhibitors (chloroquine or 3-methyladenine) block rapamycin-induced removal of Aβ, further strengthening the assumption that rapamycin acts by inducing autophagy in AD models (Caccamo, Majumder, Richardson, Strong, & Oddo, 2010;Simonovitch et al, 2016). Despite these findings, other studies reported the effects of rapamycin in AD to be mediated by mechanisms other than autophagy.…”

The Contribution of Astrocyte Autophagy to Systemic Metabolism

“…In the case of astrocytes, autophagy represents an essential mechanism to face the lack of nutrients. Several studies have shown that amino acid deprivation or ATP depletion activates autophagy in cultured astrocytes [58,59]. The blockade of autophagy using chloroquine (a drug that impairs autophagosome fusion with lysosomes) exacerbates astrocyte cell death after nutrient deprivation [60].…”