BIN1 localization is distinct from Tau tangles in Alzheimer’s disease

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 have 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.

BIN1 protein isoforms are differentially expressed in astrocytes, neurons, and microglia: neuronal and astrocyte BIN1 are implicated in tau pathology

“…While this study focused the expression of BIN1 in three major cell types in the grey matter of DLPFC (https://doi.org/10.1101/566307), the expression of BIN1 by mature oligodendrocytes and its involvement in oligodendrocyte myelination has been described in the white matter [12]. These investigators reported that oligodendrocytes, which are enriched in white matter, mainly express BIN1 isoform 9 [42], which could explain why our exon-specific antibodies did not detect BIN1 isoforms expressed by oligodendrocytes, since exons 7, 11, 13 or 16 are not contained within isoform 9.…”

A Bayesian approach to mediation analysis predicts 206 causal target genes in Alzheimer’s disease

“…Instead, cis-eQTLs within 1Mb window cover that region and extend through non-zero LD effect of CYP27C1 to nearly 2Mb around the GWAS locus (Fig 3e). The contribution of BIN1 to AD is somewhat controversial [65][66][67] , and we expect follow-up mediation analysis with cell type-specific eQTLs will further clarify the mechanisms.…”

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

“…The exact consequence of the LOAD-associated SNPs identified at the BIN1 locus remains unknown. Previous studies have reported conflicting findings on BIN1 protein expression levels in AD (9 -12) and how it correlates with amyloid and tau pathology (9,10,(13)(14)(15), whereas BIN1 mRNA levels have been shown to be altered in disease and correlate with age of disease onset and disease duration (16).…”