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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 45; pp. E9665 - E9674
• Main Authors: Andrew, Robert J., Fernandez, Celia G., Stanley, Molly, Jiang, Hong, Nguyen, Phuong, Rice, Richard C., Buggia-Prévot, Virginie, De Rossi, Pierre, Vetrivel, Kulandaivelu S., Lamb, Raza, Argemi, Arnau, Allaert, Emilie S., Rathbun, Elle M., Krause, Sofia V., Wagner, Steven L., Parent, Angèle T., Holtzman, David M., Thinakaran, Gopal
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 07-11-2017
• Series: PNAS Plus
• Subjects: Alanine; Alzheimer's disease; Amyloid precursor protein; Amyloidosis; Animal models; Aspartic endopeptidase; Axon guidance; Axons; Biological Sciences; Brain; Cognition & reasoning; Cognitive ability; Cysteine; Dendritic spines; In vivo methods and tests; Lesions; Localization; Memory; Mice; Neurodegenerative diseases; Neurons; Palmitoylation; Pathogenesis; Peptides; PNAS Plus; Proteins; Proteolysis; Residues; Rodents; Spine; Substrates; Transgenic mice; β-Amyloid; β-Site APP-cleaving enzyme 1; axonal transport; neurodegeneration; PDAPP; 5XFAD; dystrophic neurite
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1708568114

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.