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.

Highlights

  • Genome-wide association studies have identified Bridging INtegrator-1 (BIN1) within the second most significant susceptibility locus in late-onset Alzheimer’s disease (AD)

  • Our study reveals BIN1 immunolabeling of morphologically distinct cell types from those stained by Ionized calcium-binding adapter molecule 1 (Iba1), CD45, and CD68, arguing against detectable levels of BIN1 expression in mouse or human brain microglia or macrophages in situ (Figs. 3, 6, 8, and Additional file 10: Figure S6)

  • Multiple BIN1 isoforms are expressed in the human brain and there are significant changes in the levels of select BIN1 isoforms in the brains of individuals with late-onset AD

Read more

Summary

Introduction

Genome-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. BIN1 was first identified as a protein that interacted with the N-terminus of the MYC oncoprotein [2], and cloned based on sequence similarity to Amphiphysin 1, a protein predominantly expressed in the brain [3,4,5,6,7,8]. Based on sequence similarity to Amphiphysin 1, it has been proposed that BIN1 might function in synaptic vesicle endocytosis [9]. Alternate splicing of the 20 exons in BIN1 gene generates at least 10 transcripts encoding ubiquitous and tissue-specific isoforms, which differ in their tissue distribution and in subcellular localization and cellular function [2, 4,5,6, 12, 13]

Methods
Results
Discussion
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call