BIN1 favors the spreading of Tau via extracellular vesicles

Andrea Crotti,Kathleen M Mcavoy,Taylor L Reynolds,Richard M Ransohoff,Michael Peterson,Isin Dalkilic-Liddle,Galina Marsh,Ayla Ergun,Suzanne Szak,Andrew Cameron,Hameetha Rajamohamend Sait,Karol Estrada,Ellen Cahir-Mcfarland,Luke Jandreski

doi:10.1038/s41598-019-45676-0

Abstract

Despite Bridging INtegrator 1 (BIN1) being the second most statistically-significant locus associated to Late Onset Alzheimer’s Disease, its role in disease pathogenesis remains to be clarified. As reports suggest a link between BIN1, Tau and extracellular vesicles, we investigated whether BIN1 could affect Tau spreading via exosomes secretion. We observed that BIN1-associated Tau-containing extracellular vesicles purified from cerebrospinal fluid of AD-affected individuals are seeding-competent. We showed that BIN1 over-expression promotes the release of Tau via extracellular vesicles in vitro as well as exacerbation of Tau pathology in vivo in PS19 mice. Genetic deletion of Bin1 from microglia resulted in reduction of Tau secretion via extracellular vesicles in vitro, and in decrease of Tau spreading in vivo in male, but not female, mice, in the context of PS19 background. Interestingly, ablation of Bin1 in microglia of male mice resulted in significant reduction in the expression of heat-shock proteins, previously implicated in Tau proteostasis. These observations suggest that BIN1 could contribute to the progression of AD-related Tau pathology by altering Tau clearance and promoting release of Tau-enriched extracellular vesicles by microglia.

Highlights

Despite Bridging INtegrator 1 (BIN1) being the second most statistically-significant locus associated to Late Onset Alzheimer’s Disease, its role in disease pathogenesis remains to be clarified
We report that BIN1 and Tau are present in seeding-competent Extracellular Vesicles (EVs) purified from Cerebrospinal Fluid (CSF) of Alzheimer’s Disease (AD)-affected individuals
To gain insights into the mechanism of action of BIN1-associated genetic variants in AD etiology, we looked at their effect in relation to Aβ levels, as well as the amount of pTau[181] (Threonine 181) in CSF (Methods)[22]

Summary

Introduction

Despite Bridging INtegrator 1 (BIN1) being the second most statistically-significant locus associated to Late Onset Alzheimer’s Disease, its role in disease pathogenesis remains to be clarified. Ablation of Bin[1] in microglia of male mice resulted in significant reduction in the expression of heat-shock proteins, previously implicated in Tau proteostasis These observations suggest that BIN1 could contribute to the progression of AD-related Tau pathology by altering Tau clearance and promoting release of Tauenriched extracellular vesicles by microglia. In the last few years, it has been proposed that progressive Tau pathology may be associated with “prion-like” spreading between brain regions which are functionally connected[3] In this view, hyper-phosphorylated and misfolded Tau aggregates give rise to conformation-dependent “seeds” that promote a templated propagation of intracellular aggregated deposits. SNPs in the locus harboring Bridging INtegrator 1 (BIN1) gene show the strongest association with AD, after Apolipoprotein E (APOE)[23]

Methods

Results

Conclusion