Oxidative inactivation of amyloid beta-degrading proteases by cholesterol-enhanced mitochondrial stress

Redox Biology
Cristina de DiosAnna Colell

Abstract

Familial early-onset forms of Alzheimer's disease (AD) are linked to overproduction of amyloid beta (Aβ) peptides, while decreased clearance of Aβ is the driving force leading to its toxic accumulation in late-onset (sporadic) AD. Oxidative modifications and defective function have been reported in Aβ-degrading proteases such as neprilysin (NEP) and insulin-degrading enzyme (IDE). However, the exact mechanisms that regulate the proteolytic clearance of Aβ and its deficits are largely unknown. We have previously showed that cellular cholesterol loading, by depleting the mitochondrial GSH (mGSH) content, stimulates Αβ-induced mitochondrial oxidative stress and promotes AD-like pathology in APP-PSEN1-SREBF2 mice. Here, using the same AD mouse model we examined whether cholesterol-enhanced mitochondrial oxidative stress affects NEP and IDE function. We found that brain extracts from APP-PSEN1-SREBF2 mice displayed increased presence of oxidatively modified forms of NEP and IDE, associated with impaired enzymatic activities. Both alterations were substantially recovered after an in vivo treatment with the cholesterol-lowering agent 2-hydroxypropyl-β-cyclodextrin. The recovery of the proteolytic activity after treatment was accompani...Continue Reading

Citations

Sep 30, 2020·Antioxidants·Montserrat MaríAnna Colell
Mar 10, 2021·Molecular Neurodegeneration·Vicente Roca-AgujetasAnna Colell
Nov 30, 2021·Journal of the American Chemical Society·Dangliang LiuSuwei Dong

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Methods Mentioned

BETA
PCR
genotyping
ELISA
Assay
ELISAs
immunoprecipitation
transgenic
electron microscopy

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