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

Robert J. Andrew, 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, Gopal Thinakaran

Research output: Contribution to journalArticlepeer-review

46 Scopus citations


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.

Original languageEnglish
Pages (from-to)E9665-E9674
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number45
StatePublished - Nov 7 2017


  • 5XFAD
  • Axonal transport
  • Dystrophic neurite
  • Neurodegeneration


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