2017
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, and Gopal Thinakaran
Abstract: Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by pathological brain lesions and a decline in cognitive function. b-amyloid peptides (Ab), derived from proteolytic processing of amyloid precursor protein (APP), play a central role in AD pathogenesis. β-site APP converting enzyme 1 (BACE1), the transmembrane aspartyl protease which initiates Ab 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 post-translational 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 Ab levels were similar, synaptic activity-induced endogenous Ab 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 the 5XFAD mice. Using transgenic mouse models, these results demonstrate that intrinsic post-translational S-palmitoylation of BACE1 has a significant impact on amyloid pathogenesis and the consequent cognitive decline.
BIN1 localization is distinct from Tau tangles in Alzheimer’s disease
Pierre De Rossi, Virginie Buggia-Prevot, Robert J Andrew, Sofia V Krause, Elizabeth Woo, Peter T Nelson, Peter Pytel, Gopal Thinakaran
Abstract: BIN1 is the second most significant Alzheimer’s disease (AD) risk factor gene identified through genome-wide association studies. BIN1 is an adaptor protein that can bind to several proteins including c-Myc, clathrin, adaptor protein-2, and dynamin. BIN1 is widely expressed in the brain and peripheral tissue as ubiquitous and tissue-specific alternatively spliced isoforms that regulate membrane dynamics and endocytosis in multiple cell types. The function of BIN1 in the brain and the mechanism(s) by which AD-associated BIN1 alleles increase the risk for the disease are not known. BIN1 has been shown to interact with Tau, and two studies reported a positive correlation between BIN1 expression and neurofibrillary tangle pathology in AD. However, an inverse correlation between BIN1 expression and Tau propagation has also been reported. Moreover, there have been conflicting reports on whether BIN1 is present in tangles. A recent study characterized predominant BIN1 expression in mature oligodendrocytes in the gray matter and the white matter in rodent, and the human brain. Here, we examined BIN1 localization in the brains of patients with AD using immunohistochemistry and immunofluorescence techniques to analyze BIN1 cellular expression in relation to cellular markers and pathological lesions in AD. We report that BIN1 immunoreactivity in human AD is not associated with neurofibrillary tangles or senile plaques. Moreover, our results show that BIN1 is not expressed by resting and activated microglia, astrocytes, or macrophages in human AD. In accordance with a recent report, low-level de novo BIN1 expression can be observed in a subset of neurons in the AD brain. Further investigations are warranted to understand the complex cellular mechanisms underlying the observed correlation between BIN1 expression and the severity of tangle pathology in AD.