Cholesterol impairs autophagy-mediated clearance of amyloid beta while promoting its secretion

Abstract

Macroautophagy/autophagy failure with the accumulation of autophagosomes is an early neuropathological feature of Alzheimer disease (AD) that directly affects amyloid beta (Aβ) metabolism. Although loss of presenilin 1 function has been reported to impair lysosomal function and prevent autophagy flux, the detailed mechanism leading to autophagy dysfunction in AD remains to be elucidated. The resemblance between pathological hallmarks of AD and Niemann-Pick Type C disease, including endosome-lysosome abnormalities and impaired autophagy, suggests cholesterol accumulation as a common link. Using a mouse model of AD (APP-PSEN1-SREBF2 mice), expressing chimeric mouse-human amyloid precursor protein with the familial Alzheimer Swedish mutation (APP695swe) and mutant presenilin 1 (PSEN1-dE9), together with a dominant-positive, truncated and active form of SREBF2/SREBP2 (sterol regulatory element binding factor 2), we demonstrated that high brain cholesterol enhanced autophagosome formation, but disrupted its fusion with endosomal-lysosomal vesicles. The combination of these alterations resulted in impaired degradation of Aβ and endogenous MAPT (microtubule associated protein tau), and stimulated autophagy-dependent Aβ secretion. Exacerbated Aβ-induced oxidative stress in APP-PSEN1-SREBF2 mice, due to cholesterol-mediated depletion of mitochondrial glutathione/mGSH, is critical for autophagy induction. In agreement, in vivo mitochondrial GSH recovery with GSH ethyl ester, inhibited autophagosome synthesis by preventing the oxidative inhibition of ATG4B deconjugation activity exerted by Aβ. Moreover, cholesterol-enrichment within the endosomes-lysosomes modified the levels and membrane distribution of RAB7A and SNAP receptors (SNAREs), which affected its fusogenic ability. Accordingly, in vivo treatment with 2-hydroxypropyl-β-cyclodextrin completely rescued these alterations, making it a potential therapeutic tool for AD.

Autophagy induction in the treatment of Alzheimer's disease

“…Accordingly, a drug candidate against Niemann-Pick C1 (2-hydroxypropyl-b-cyclodextrin), which normalizes cellular cholesterol levels, could reverse the detrimental effect of high cholesterol on autophagy and Aβ accumulation (Barbero-Camps et al, 2018). Together, these results highlight the cholesterol pathway as promising target for autophagic modulation in AD.…”

“…Another evidence supporting the role of autophagy following statins treatment in the context of AD is that high brain cholesterol, whose levels are reduced by statins, was shown to impair autophagy resulting in increased Aβ burden in AD mice model (Barbero‐Camps et al, ). Accordingly, a drug candidate against Niemann‐Pick C1 (2‐hydroxypropyl‐b‐cyclodextrin), which normalizes cellular cholesterol levels, could reverse the detrimental effect of high cholesterol on autophagy and Aβ accumulation (Barbero‐Camps et al, ). Together, these results highlight the cholesterol pathway as promising target for autophagic modulation in AD.…”

Cholesterol metabolism plays a crucial role in the regulation of autophagy for cell differentiation of granular convoluted tubules in male mouse submandibular glands

“…A growing number of studies indicate that autophagy and autophagyrelated molecules play a crucial role in cell differentiation (Mizushima and Levine, 2010). In addition, a relationship between cholesterol metabolism and autophagy regulation has been suggested in several pathological conditions (Barbero-Camps et al, 2018;Cheng et al, 2006;Seo et al, 2011); however, the nature of this relationship has not yet been clarified in development and organogenesis.…”

CHIP modulates APP‐induced autophagy‐dependent pathological symptoms in Drosophila

“…On the other hand, autophagy deficiency impedes Aβ secretion and reduces extracellular Aβ accumulation and plaque burden in AD mice (Nilsson et al, ). Consistently, high brain cholesterol impairs Aβ degradation but stimulates autophagy‐dependent Aβ secretion and amyloid deposit formation (Barbero‐Camps et al, ). In this study, we found that blocking autophagy not only reduces Aβ production and accumulation, but also suppresses APP‐induced morphological, behavioral, and cognitive defects.…”