Lack of BACE1 S-palmitoylation reduces amyloid burden and mitigates memory deficits in transgenic mouse models of Alzheimer's disease

Proceedings of the National Academy of Sciences of the United States of America
Robert J AndrewGopal Thinakaran

Abstract

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by pathological brain lesions and a decline in cognitive function. β-Amyloid peptides (Aβ), derived from proteolytic processing of amyloid precursor protein (APP), play a central role in AD pathogenesis. β-Site APP cleaving enzyme 1 (BACE1), the transmembrane aspartyl protease which initiates Aβ production, is axonally transported in neurons and accumulates in dystrophic neurites near cerebral amyloid deposits in AD. BACE1 is modified by S-palmitoylation at four juxtamembrane cysteine residues. S-palmitoylation is a dynamic posttranslational modification that is important for trafficking and function of several synaptic proteins. Here, we investigated the in vivo significance of BACE1 S-palmitoylation through the analysis of knock-in mice with cysteine-to-alanine substitution at the palmitoylated residues (4CA mice). BACE1 expression, as well as processing of APP and other neuronal substrates, was unaltered in 4CA mice despite the lack of BACE1 S-palmitoylation and reduced lipid raft association. Whereas steady-state Aβ levels were similar, synaptic activity-induced endogenous Aβ production was not observed in 4CA mice. Furthermore, we report a s...Continue Reading

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Citations

Dec 24, 2017·Molecular Neurodegeneration·Joanna L Jankowsky, Hui Zheng
Dec 25, 2019·Biochemical Society Transactions·Niall J FraserWilliam Fuller
Dec 22, 2019·Chembiochem : a European Journal of Chemical Biology·Madhu RameshThimmaiah Govindaraju
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Oct 24, 2020·Journal of Cellular Physiology·Jiayu JinDan Meng
Jan 13, 2021·Molecular Brain·Benjun Ji, Małgorzata Skup
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Sep 16, 2021·Journal of Biochemistry·Keisuke KomakiShin-Ichi Hisanaga
Nov 6, 2021·Biology of the Cell·Maxime Jansen, Bruno Beaumelle

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