Alzheimer’s disease risk geneBIN1induces Tau-dependent network hyperexcitability

Abstract

Genome-wide association studies identified the BIN1 locus as a leading modulator of genetic risk in Alzheimer's disease (AD). One limitation in understanding BIN1's contribution to AD is its unknown function in the brain. AD-associated BIN1 variants are generally noncoding and likely change expression. Here, we determined the effects of increasing expression of the major neuronal isoform of human BIN1 in cultured hippocampal neurons. Higher BIN1 induced network hyperexcitability on multielectrode arrays, increased frequency of synaptic transmission, and elevated calcium transients, indicating that increasing BIN1 drives greater neuronal activity. In exploring the mechanism of these effects on neuronal physiology, we found that BIN1 interacted with L-type voltage-gated calcium channels (LVGCCs) and that BIN1-LVGCCs interactions were modulated by Tau in vitro and in vivo. Finally, Tau reduction prevented BIN1-induced network hyperexcitability. These data shed light on BIN1's neuronal function and suggest that it may contribute to Tau-dependent hyperexcitability in AD.Genetic discoveries have provided critical insights into potential mechanisms of Alzheimer's disease (AD), the most common neurodegenerative disease. Mutations in APP, PSEN1, or PSEN2 cause early-onset, autosomal dominantly inherited AD, but are quite rare. Several more common genetic variants that increase AD risk to differing degrees have been identified. Among these, variants near BIN1 have particularly high population attributable risk, because the risk allele is highly prevalent (~40% allele frequency for the index SNP, rs6733839) and has a relatively large effect size (odds ratio: 1.20; 95% confidence interval: 1.17-1.23) (Kunkle et al., 2019).BIN1 was first linked to AD in early genome-wide associated studies (GWAS) (Harold et al., 2009;Seshadri et al., 2010) and remains second only to APOE in genomewide significance in the recent meta-analysis of 94,437 individuals by the International Genomics of Alzheimer's Disease Project (Kunkle et al., 2019). This association has been replicated in datasets with subjects from diverse genetic backgrounds (Carrasquillo

Delivering progranulin to neuronal lysosomes protects against excitotoxicity

“…BrainPhys media (Stem Cell Technologies) was used instead of Neurobasal for media changes on DIV4 (with addition of Ara-C) and DIV9. At DIV 12, neurons were recorded on an Axion system as described previously (97). Neurons were recorded for 20 minutes for a baseline recording, then 50 uM NMDA was applied and neuronal firing was recorded for 20 more minutes.…”

“…Neurons were recorded for 20 minutes for a baseline recording, then 50 uM NMDA was applied and neuronal firing was recorded for 20 more minutes. Electrical activity was analyzed with Plexon Offline Sorter and NeuroExplorer to determine action potential frequency as described previously (97). Neurons were defined to be in depolarization block if there were zero action potentials in the last five minutes of recording after NMDA application.…”

The Alzheimer’s disease risk gene BIN1 modulates neural network activity via the regulation of L-type calcium channel expression in human-induced neurons

“…BIN1 may contribute to the regulation of neuronal and circuit activity through numerous mechanisms, including increased APP processing and production of amyloid-beta peptides (Miyagawa et al, 2016;Ubelmann et al, 2017), alterations in Tau phosphorylation and propagation (Calafate et al, 2016;Lasorsa et al, 2018;Sartori et al, 2019;Voskobiynyk et al, 2020), subcellular localization of voltage-gated calcium channels (Hong et al, 2010;Voskobiynyk et al, 2020) and recycling of synaptic vesicles/AMPA receptors (Schürmann et al, 2019;De Rossi et al, 2020). Accordingly, conditional deletion of BIN1 in neurons of the adult mice hippocampus, leads to altered frequency of mini excitatory post-synaptic currents (mEPSC), likely due to an impaired presynaptic release probability and slower depletion of neurotransmitters (De Rossi et al, 2020).…”

The BIN1 rs744373 Alzheimer's disease risk SNP is associated with faster Aβ‐associated tau accumulation and cognitive decline

“…The BIN1 gene encodes the nucleoplasmic adaptor protein BIN1, which is predominantly expressed in brain and muscle tissue 6 and is involved in the regulation of membrane curvature, 7 clathrin‐mediated endocytosis, 8,9 presynaptic vesicle release, 10 and neuronal excitability 11,12 . Previous pre‐clinical, 8,9,13 post mortem , 13–15 and biomarker studies 8,16,17 demonstrated BIN1 involvement in the development of tau pathology, which is considered a major driver of neurodegeneration 18 and cognitive decline in AD 19 .…”