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TitleLack of BACE1 S-palmitoylation reduces amyloid burden and mitigates memory deficits in transgenic mouse models of Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2017
AuthorsAndrew, Robert J., Celia G. Fernandez, Molly Stanley, Hong Jiang, Phuong Nguyen, Richard C. Rice, Virginie Buggia-Prévot, Pierre De Rossi, Kulandaivelu S. Vetrivel, Raza Lamb, Arnau Argemi, Emilie S. Allaert, Elle M. Rathbun, Sofia V. Krause, Steven L. Wagner, Angèle T. Parent, David M. Holtzman, and Gopal Thinakaran
JournalProc Natl Acad Sci U S A
Volume114
Issue45
PaginationE9665-E9674
Date Published2017 11 07
ISSN1091-6490
KeywordsAlzheimer Disease, Amyloid, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Amyloid Precursor Protein Secretases, Amyloidogenic Proteins, Amyloidosis, Animals, Aspartic Acid Endopeptidases, Axons, Brain, Disease Models, Animal, Female, Lipoylation, Male, Memory Disorders, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Protein Processing, Post-Translational
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 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.

DOI10.1073/pnas.1708568114
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID29078331
PubMed Central IDPMC5692556
Grant ListS10 OD010649 / OD / NIH HHS / United States
R01 NS055223 / NS / NINDS NIH HHS / United States
T32 GM007839 / GM / NIGMS NIH HHS / United States
P01 NS080675 / NS / NINDS NIH HHS / United States
R21 AG046710 / AG / NIA NIH HHS / United States
R01 AG019070 / AG / NIA NIH HHS / United States
R21 AG051230 / AG / NIA NIH HHS / United States