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


ABSTRACT: Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by pathological brain lesions and a decline in cognitive function. ?-Amyloid peptides (A?), derived from proteolytic processing of amyloid precursor protein (APP), play a central role in AD pathogenesis. ?-Site APP cleaving enzyme 1 (BACE1), the transmembrane aspartyl protease which initiates A? 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 A? levels were similar, synaptic activity-induced endogenous A? production was not observed in 4CA mice. Furthermore, we report a significant reduction of cerebral amyloid burden and BACE1 accumulation in dystrophic neurites in the absence of BACE1 S-palmitoylation in mouse models of AD amyloidosis. Studies in cultured neurons suggest that S-palmitoylation is required for dendritic spine localization and axonal targeting of BACE1. Finally, the lack of BACE1 S-palmitoylation mitigates cognitive deficits in 5XFAD mice. Using transgenic mouse models, these results demonstrate that intrinsic posttranslational S-palmitoylation of BACE1 has a significant impact on amyloid pathogenesis and the consequent cognitive decline.

SUBMITTER: Andrew RJ 

PROVIDER: S-EPMC5692556 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Andrew Robert J RJ   Fernandez Celia G CG   Stanley Molly M   Jiang Hong H   Nguyen Phuong P   Rice Richard C RC   Buggia-Prévot Virginie V   De Rossi Pierre P   Vetrivel Kulandaivelu S KS   Lamb Raza R   Argemi Arnau A   Allaert Emilie S ES   Rathbun Elle M EM   Krause Sofia V SV   Wagner Steven L SL   Parent Angèle T AT   Holtzman David M DM   Thinakaran Gopal G  

Proceedings of the National Academy of Sciences of the United States of America 20171023 45


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  ...[more]

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