Tau‐dependent regulation of neuronal activity by the Alzheimer's disease risk gene BIN1: Molecular and cell biology/tau. (7th December 2020)

• Record Type: Journal Article
• Authors: Voskobiynyk, Yuliya; Roth, Jonathan R.; Cochran, J. Nicholas; Rush, Travis; Carullo, Nancy V.N.; Waqas, Mohammad; Vollmer, Rachael; McMahon, Lori L.; Day, Jeremy J.; Roberson, Erik D.
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 3
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.045382
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Alzheimer's disease (AD) affects about five million Americans and the underlying causes of the disease remain uncertain. Genome wide association studies (GWAS) have identified bridging integrator 1 ( BIN1 ) as one of the leading genetic risk factors in AD. Neurons express unique BIN1 isoforms, but their function is unknown. Thus, one key question that may contribute to a deeper understanding of AD pathophysiology is how BIN1 affects neuronal function. Methods: To address this question, we determined the effects of expressing human BIN1 neuronal isoform 1 in primary hippocampal cultures. Results: First, we observed that higher BIN1 increased spike and burst frequency using multielectrode arrays. On patch‐clamp recordings of transduced neurons, higher BIN1 increased frequency of both excitatory and inhibitory synaptic transmission. Higher BIN1 also increased calcium spikes in neurons co‐transfected with the calcium indicator GCaMP6f. To understand the potential mechanism of increased calcium influx, we explored potential interactions with L‐type voltage gated calcium channels (LVGCCs). BIN1 interacted with LVGCCs in neurons in a Tau‐dependent manner, assessed by both co‐immunoprecipitation and proximity ligation assay. Finally, using a high throughput multielectrode array system, we showed that Tau reduction prevents network hyperexcitability induced by BIN1. Conclusions: Together, these data show Tau‐dependent regulation of neuronal activity by the Alzheimer's disease risk gene BIN1 and generate fundamental insights about the mechanistic role BIN1 may play in AD.