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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.

SUBMITTER: De Rossi P

PROVIDER: S-EPMC5823513 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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BIN1 localization is distinct from Tau tangles in Alzheimer's disease.

De Rossi Pierre P Buggia-Prevot Virginie V Andrew Robert J RJ Krause Sofia V SV Woo Elizabeth E Nelson Peter T PT Pytel Peter P Thinakaran Gopal G

Matters 20170112

<i>BIN1</i> 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. <i>BIN1</i> 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 th ...[more]

PMID: 29479533

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Project description:BackgroundMultimerization is a key process in prion-like disorders such as Alzheimer's disease (AD), since it is a requirement for self-templating tau and beta-amyloid amyloidogenesis. AT8-immunohistochemistry for hyperphosphorylated tau is currently used for the diagnosis and staging of tau pathology. Given that tau-tau interactions can occur in the absence of hyperphosphorylation or other post-translational modifications (PTMs), the direct visualization of tau multimerization could uncover early pathological tau multimers.MethodsHere, we used bimolecular fluorescent complementation, rapamycin-dependent FKBP/FRB-tau interaction and transmission electron microscopy to prove the in vitro specificity of tau-proximity ligation assay (tau-PLA). We then analyzed MAPT KO and P301S transgenic mice, and human hippocampus and temporal isocortex of all Braak stages with tau-PLA and compared it with immunohistochemistry for the diagnostic antibody AT8, the early phosphorylation-dependent AT180, and the conformational-dependent antibody MC1. Finally, we performed proteinase-K treatment to infer the content of amyloidogenic beta-sheet fold.ResultsOur novel tau-proximity ligation assay (tau-PLA) directly visualized tau-tau interactions in situ, and exclusively recognized tau multimers but not monomers. It elicited no signal in MAPT KO mouse brains, but extensively labelled P301S transgenic mice and AD brain. Two groups of structures were detected, a previously unreported widespread small-sized diffuse pathology and large, neurofibrillary-like lesions. Tau-PLA-labelled diffuse pathology appeared from the earliest Braak stages, mostly unaccompanied by tangle-like tau-immunohistochemistry, being significantly more sensitive than any small-sized dot-/thread-like pathology labelled by AT180-, AT8- and MC1-immunohistochemistry in most regions quantified at stages 0-II. Tau-PLA-labelled diffuse pathology was extremely sensitive to Proteinase-K, in contrast to large lesions.ConclusionsTau-PLA is the first method to directly visualize tau multimers both in vitro and in situ with high specificity. We find that tau multimerization appears extensively from the earliest presymptomatic Braak stages as a previously unreported type of diffuse pathology. Importantly, in our study multimerization is the earliest detectable molecular event of AD tau pathology. Our findings open a new window to the study of early tau pathology, with potential implications in early diagnosis and the design of therapeutic strategies.

Project description: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.

Dataset Information

BIN1 localization is distinct from Tau tangles in Alzheimer's disease.

Publications

BIN1 localization is distinct from Tau tangles in Alzheimer's disease.

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