Dataset Information

Aberrant accrual of BIN1 near Alzheimer's disease amyloid deposits in transgenic models.

ABSTRACT: Bridging integrator 1 (BIN1) is the most significant late-onset Alzheimer's disease (AD) susceptibility locus identified via genome-wide association studies. BIN1 is an adaptor protein that regulates membrane dynamics in the context of endocytosis and membrane remodeling. An increase in BIN1 expression and changes in the relative levels of alternatively spliced BIN1 isoforms have been reported in the brains of patients with AD. BIN1 can bind to Tau, and an increase in BIN1 expression correlates with Tau pathology. In contrast, the loss of BIN1 expression in cultured cells elevates Aβ production and Tau propagation by insfluencing endocytosis and recycling. Here, we show that BIN1 accumulates adjacent to amyloid deposits in vivo. We found an increase in insoluble BIN1 and a striking accrual of BIN1 within and near amyloid deposits in the brains of multiple transgenic models of AD. The peri-deposit aberrant BIN1 localization was conspicuously different from the accumulation of APP and BACE1 within dystrophic neurites. Although BIN1 is highly expressed in mature oligodendrocytes, BIN1 association with amyloid deposits occurred in the absence of the accretion of other oligodendrocyte or myelin proteins. Finally, super-resolution microscopy and immunogold electron microscopy analyses highlight the presence of BIN1 in proximity to amyloid fibrils at the edges of amyloid deposits. These results reveal the aberrant accumulation of BIN1 is a feature associated with AD amyloid pathology. Our findings suggest a potential role for BIN1 in extracellular Aβ deposition in vivo that is distinct from its well-characterized function as an adaptor protein in endocytosis and membrane remodeling.

SUBMITTER: De Rossi P

PROVIDER: S-EPMC6542723 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Aberrant accrual of BIN1 near Alzheimer's disease amyloid deposits in transgenic models.

De Rossi Pierre P Andrew Robert J RJ Musial Timothy F TF Buggia-Prevot Virginie V Xu Guilian G Ponnusamy Moorthi M Ly Han H Krause Sofia V SV Rice Richard C RC de l'Estoile Valentine V Valin Tess T Salem Someya S Despa Florin F Borchelt David R DR Bindokas Vytas P VP Nicholson Daniel A DA Thinakaran Gopal G

Brain pathology (Zurich, Switzerland) 20181227 4

Bridging integrator 1 (BIN1) is the most significant late-onset Alzheimer's disease (AD) susceptibility locus identified via genome-wide association studies. BIN1 is an adaptor protein that regulates membrane dynamics in the context of endocytosis and membrane remodeling. An increase in BIN1 expression and changes in the relative levels of alternatively spliced BIN1 isoforms have been reported in the brains of patients with AD. BIN1 can bind to Tau, and an increase in BIN1 expression correlates ...[more]

PMID: 30506549

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Project description:Beta-amyloid (Aβ) plaque pathology is one of the most prominent histopathological feature of Alzheimer's disease (AD). The exact pathogenic mechanisms linking Aβ to AD pathogenesis remain however not fully understood. Recent advances in amyloid-targeting pharmacotherapies highlight the critical relevance of Aβ aggregation for understanding the molecular basis of AD pathogenesis. We developed a novel, integrated, tetramodal chemical imaging paradigm for acquisition of trimodal mass spectrometry imaging (MSI) and interlaced fluorescent microscopy from a single tissue section. We used this approach to comprehensively investigate lipid-Aβ correlates at single plaques in two different mouse models of AD (tgAPPSwe and tgAPPArcSwe) with varying degrees of intrinsic properties affecting amyloid aggregation. Integration of the multimodal imaging data and multivariate data analysis identified characteristic patterns of plaque-associated lipid- and peptide localizations across both mouse models. Correlative fluorescence microscopy using structure-sensitive amyloid probes identified intra-plaque structure-specific lipid- and Aβ patterns, including Aβ 1-40 and Aβ 1-42 along with gangliosides (GM), phosphoinositols (PI), conjugated ceramides (CerP and PE-Cer), and lysophospholipids (LPC, LPA, and LPI). Single plaque correlation analysis across all modalities further revealed how these distinct lipid species were associated with Aβ peptide deposition across plaque heterogeneity, indicating different roles for those lipids in plaque growth and amyloid fibrillation, respectively. Here, conjugated ceramide species correlated with Aβ core formation indicating their involvement in initial plaque seeding or amyloid maturation. In contrast, LPI and PI were solely correlated with general plaque growth. In addition, GM1 and LPC correlated with continuous Aβ deposition and maturation. The results highlight the potential of this comprehensive multimodal imaging approach and implement distinct lipids in amyloidogenic proteinopathy.

Dataset Information

Aberrant accrual of BIN1 near Alzheimer's disease amyloid deposits in transgenic models.

Publications

Aberrant accrual of BIN1 near Alzheimer's disease amyloid deposits in transgenic models.

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