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. 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.

Role of Post‐translational Modifications in Alzheimer's Disease

“…Interestingly, the absence of S‐palmitoylation in BACE1 alleviates memory loss in Tg mice, to reveal the significant role of this PTM in localisation to specific compartments and amyloidogenesis. This study contradicts a few earlier reports (in vitro), but provides direct evidence in vivo …”

Reduction of the expression of the late-onset Alzheimer’s disease (AD) risk-factor BIN1 does not affect amyloid pathology in an AD mouse model

“…For amyloid burden quantification (thioflavin S and mAb 3D6), five to eight sections per mouse were analyzed using ImageJ as described previously (58).…”

“…The total number of arms entries (counted when all four limbs had entered the arm of the maze) and the sequence in which arms were entered were recorded. The percentage of spontaneous alternations was calculated and analyzed as described previously (58).…”

“…Contextual fear conditioning was performed on 4-monthold mice in a Coulbourn HABITEST isolation cubicle with shocks applied using a Coulbourn Precision Animal Shocker (Harvard Apparatus) as described (58). Analysis of recordings from the video-based system was performed using Freez-eFrame 4 software (Actimetrics) as described previously (58).…”

Cholesterol and ApoE in Alzheimer’s disease

“…Other studies demonstrated that the palmitoylation of APP regulates its distribution in lipid rafts and its amyloidogenic processing (Bhattacharyya et al, 2013). The palmitoylation of BACE1 also regulates its enrichment in lipid rafts and although it does not affect its steady-state processing activity, it controls the synaptic activity-induced production of Ab (Vetrivel et al, 2009;Andrew et al, 2017).…”