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

Pierre De Rossi, Robert J. Andrew, Timothy F. Musial, Virginie Buggia-Prevot, Guilian Xu, Moorthi Ponnusamy, Han Ly, Sofia V. Krause, Richard C. Rice, Valentine de l’Estoile, Tess Valin, Someya Salem, Florin Despa, David R. Borchelt, Vytas P. Bindokas, Daniel A. Nicholson, Gopal Thinakaran

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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.

Original languageEnglish
Pages (from-to)485-501
Number of pages17
JournalBrain Pathology
Volume29
Issue number4
DOIs
StatePublished - Jul 2019

Bibliographical note

Funding Information:
This study was supported by Cure Alzheimer’s Fund (GT), National Multiple Sclerosis Society (GT), Alzheimer’s Association (PDR and FD), American Stroke Association (FD), and National Institutes of Health grants AG019070 (GT) and AG056061 (GT and DAN), AG053999 (FD) and AG057290 (FD and GT). PDR and VPB were supported by postdoctoral fellowships from the BrightFocus Foundation. RJA was supported by an AD Research fellowship from the Illinois Department of Public Health. Confocal imaging was performed at the Integrated Microscopy Core Facility at the University of Chicago (grant S10OD010649). The use of University of Chicago’s Core Facilities was partially supported by the National Center for Advancing Translational Sciences Award 5 UL1 TR 000430-09.

Funding Information:
This study was supported by Cure Alzheimer?s Fund (GT), National Multiple Sclerosis Society (GT), Alzheimer?s Association (PDR and FD), American Stroke Association (FD), and National Institutes of Health grants AG019070 (GT) and AG056061 (GT and DAN), AG053999 (FD) and AG057290 (FD and GT). PDR and VPB were supported by postdoctoral fellowships from the BrightFocus Foundation. RJA was supported by an AD Research fellowship from the Illinois Department of Public Health. Confocal imaging was performed at the Integrated Microscopy Core Facility at the University of Chicago (grant S10OD010649). The use of University of Chicago?s Core Facilities was partially supported by the National Center for Advancing Translational Sciences Award 5 UL1 TR 000430-09. We thank the Histology Core Facility at the University of Chicago Human Tissue Resource Center for immunohistochemistry of human and mouse brain tissue. We thank Dr. Peter Pytel (University of Chicago) and University of Kentucky AD Center Neuropathology Core for providing the human brain specimens. Tg21 brain sections were kindly provided by Dr. Sangram Sisodia. We thank Dr. Charles Glabe for providing the M78 antibody and Dr. Jasvinder Atwal (Genentech) for providing anti-BACE1 human IgG. 3D6 antibody was generously provided by late Dr. Dale Schenk. We thank Dr. Dietmar R. Thal for comments on the manuscript.

Publisher Copyright:
© 2018 International Society of Neuropathology

Keywords

  • Alzheimer's disease
  • BIN1
  • GWAS
  • LOAD
  • amyloid
  • senile plaque

ASJC Scopus subject areas

  • Neuroscience (all)
  • Pathology and Forensic Medicine
  • Clinical Neurology

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