Predominant expression of Alzheimer’s disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts

Abstract

BackgroundGenome-wide association studies have identified BIN1 within the second most significant susceptibility locus in late-onset Alzheimer’s disease (AD). BIN1 undergoes complex alternative splicing to generate multiple isoforms with diverse functions in multiple cellular processes including endocytosis and membrane remodeling. An increase in BIN1 expression in AD and an interaction between BIN1 and Tau have been reported. However, disparate descriptions of BIN1 expression and localization in the brain previously reported in the literature and the lack of clarity on brain BIN1 isoforms present formidable challenges to our understanding of how genetic variants in BIN1 increase the risk for AD.MethodsIn this study, we analyzed BIN1 mRNA and protein levels in human brain samples from individuals with or without AD. In addition, we characterized the BIN1 expression and isoform diversity in human and rodent tissue by immunohistochemistry and immunoblotting using a panel of BIN1 antibodies.ResultsHere, we report on BIN1 isoform diversity in the human brain and document alterations in the levels of select BIN1 isoforms in individuals with AD. In addition, we report striking BIN1 localization to white matter tracts in rodent and the human brain, and document that the large majority of BIN1 is expressed in mature oligodendrocytes whereas neuronal BIN1 represents a minor fraction. This predominant non-neuronal BIN1 localization contrasts with the strict neuronal expression and presynaptic localization of the BIN1 paralog, Amphiphysin 1. We also observe upregulation of BIN1 at the onset of postnatal myelination in the brain and during differentiation of cultured oligodendrocytes. Finally, we document that the loss of BIN1 significantly correlates with the extent of demyelination in multiple sclerosis lesions.ConclusionOur study provides new insights into the brain distribution and cellular expression of an important risk factor associated with late-onset AD. We propose that efforts to define how genetic variants in BIN1 elevate the risk for AD would behoove to consider BIN1 function in the context of its main expression in mature oligodendrocytes and the potential for a role of BIN1 in the membrane remodeling that accompanies the process of myelination.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0124-1) contains supplementary material, which is available to authorized users.

Regulation of the interaction between the neuronal BIN1 isoform 1 and Tau proteins – role of the SH3 domain

“…In line with Tau, it has been suggested that the BIN1-Tau complex could be at the interface between the actin and microtubule network and that its deregulation may impact neuronal function [12]. Beyond Tau, since BIN1 has been observed to be mainly expressed in oligodendrocytes, this led to propose that BIN1 may deregulate myelination [19,20]. This would lead to the propagation of Tau pathology from neuron to neuron after aggregates of Tau permeabilize the endosome membrane [18].…”

“…This would lead to the propagation of Tau pathology from neuron to neuron after aggregates of Tau permeabilize the endosome membrane [18]. Beyond Tau, since BIN1 has been observed to be mainly expressed in oligodendrocytes, this led to propose that BIN1 may deregulate myelination [19,20]. Finally, BIN1 has been reported to increase cellular BACE1 levels through impaired endosomal trafficking and reduced BACE1 lysosomal degradation, resulting in increased Ab production [21].…”

Tau in Oligodendrocytes Takes Neurons in Sickness and in Health

“…Consistent with the role of BIN1 in myelination, BIN1 expression increases at the onset of postnatal brain myelination and during differentiation of cultured oligodendrocytes [105,106]. In contrast, the loss of BIN1 significantly correlates with the extent of demyelination in MS lesions [105,106]. BIN1 undergoes complex alternative splicing to generate multiple isoforms that have diverse functions [105,106].…”

Cell type-specific enhancer-promoter connectivity maps in the human brain and disease risk association

“…BIN1 has been implicated in diverse cellular processes such as endocytosis, actin dynamics, DNA repair, membrane trafficking, inflammation and apoptosis (28), and regulation of tau pathology in disease (83). Prior studies suggested that AD variants at the BIN1 locus played a putative role in neurons (83,84) and oligodendrocytes (85). However, we recently showed that BIN1 is highly expressed in ex vivo microglia compared to the whole cortex and has downstream active enhancers bound by the lineage-determining transcription factor PU.1 (15).…”