Neuronal BIN1 Regulates Presynaptic Neurotransmitter Release and Memory Consolidation

Rossi, Pierre De; Nomura, Toshihiro; Andrew, Robert J.; Masse, Nicolas Y.; Sampathkumar, Vandana; Musial, Timothy F.; Sudwarts, Ari; Recupero, Aleksandra J.; Metayer, Thomas Le; Hansen, Mitchell T.; Shim, Ha Na; Krause, Sofia V.; Freedman, David J.; Bindokas, Vytas P.; Kasthuri, Narayanan; Nicholson, Daniel A.; Contractor, Anis; Wang, Shuai

doi:10.1016/j.celrep.2020.02.026

Cited by 71 publications

(69 citation statements)

References 73 publications

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“…In addition, acute knockdown of Bin1 in primary cortical neurons reduced calcium spikes in response to NMDA (McAvoy et al, 2019). Similarly, a chronic genetic deletion of Bin1 in mice decreased mEPSCs frequency, suggesting a an effect of Bin1 on synaptic transmission (De Rossi et al, 2020). Complementary to these studies on effects of decreased Bin1 expression in mice, we found that increased human BIN1 expression increases synaptic transmission, neuronal activity, and calcium transients, and that BIN1 interacts with LVGCCs in neurons.…”

Section: Discussionsupporting

confidence: 63%

Alzheimer’s disease risk geneBIN1induces Tau-dependent network hyperexcitability

Voskobiynyk

Roth

Cochran

et al. 2020

Preprint

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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

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Section: Discussionsupporting

confidence: 63%

Alzheimer’s disease risk geneBIN1induces Tau-dependent network hyperexcitability

Voskobiynyk

Roth

Cochran

et al. 2020

Preprint

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“…BIN1 is present at pre‐ and post‐synaptic sites and in axons, as shown by super‐resolution microscopy and immuno‐electron microscopy in primary hippocampal neurons and CA3‐CA1 synapses (De Rossi et al., 2020; Schürmann et al., 2019). Post‐synaptically, BIN1 is enriched at extra‐synaptic sites within the mouse cortex (Schürmann et al., 2019); given that CME largely occurs at sites adjacent to the post‐synaptic density (PSD) (Triller & Choquet, 2005), the localisation of BIN1 supports its involvement in the CME of tau at post‐synaptic sites and suggests a role for BIN1 in its trans‐synaptic spread.…”

Section: Mechanisms For Neuronal Entry Of Taumentioning

confidence: 98%

Knockin’ on heaven’s door: Molecular mechanisms of neuronal tau uptake

La-Rocque

Moretto

Butnaru

et al. 2020

Journal of Neurochemistry

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Since aggregates of the microtubule‐binding protein tau were found to be the main component of neurofibrillary tangles more than 30 years ago, their contribution to neurodegeneration in Alzheimer's disease (AD) and tauopathies has become well established. Recent work shows that both tau load and its distribution in the brain of AD patients correlate with cognitive decline more closely compared to amyloid plaque deposition. In addition, the amyloid cascade hypothesis has been recently challenged because of disappointing results of clinical trials designed to treat AD by reducing beta‐amyloid levels, thus fuelling a renewed interest in tau. There is now robust evidence to indicate that tau pathology can spread within the central nervous system via a prion‐like mechanism following a stereotypical pattern, which can be explained by the trans‐synaptic inter‐neuronal transfer of pathological tau. In the receiving neuron, tau has been shown to take multiple routes of internalisation, which are partially dependent on its conformation and aggregation status. Here, we review the emerging mechanisms proposed for the uptake of extracellular tau in neurons and the requirements for the propagation of its pathological conformers, addressing how they gain access to physiological tau monomers in the cytosol. Furthermore, we highlight some of the key mechanistic gaps of the field, which urgently need to be addressed to expand our understanding of tau propagation and lead to the identification of new therapeutic strategies for tauopathies.

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“…BIN1 , another AD modifier identified by GWAS in humans ( 59 ), also plays a role in endocytosis ( 60 ) and has recently been shown to regulate neurotransmitter release in mouse glutamatergic neurons ( 22 ). The overexpression of Amph, the fly homologue of BIN1, led to a slight rescue in lifespan ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…However, whether BIN1 plays a role in Aβ toxicity has also not been investigated. Recently, BIN1 was shown to be involved in neurotransmitter release in mouse hippocampal neurons ( 22 ).…”

Section: Introductionmentioning

confidence: 99%

PICALM rescues glutamatergic neurotransmission, behavioural function and survival in a Drosophila model of Aβ42 toxicity

Niccoli

Ren

et al. 2020

Human Molecular Genetics

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Alzheimer’s disease (AD) is the most common form of dementia and the most prevalent neurodegenerative disease. Genome Wide Association Studies have linked PICALM to AD risk. PICALM has been implicated in Aβ42 production and turn-over, but whether it plays a direct role in modulating Aβ42 toxicity remains unclear. We found that increased expression of the Drosophila PICALM orthologue lap could rescue Aβ42 toxicity in an adult-onset model of AD, without affecting Aβ42 level. Imbalances in the glutamatergic system, leading to excessive, toxic stimulation have been associated with AD. We found that Aβ42 caused accumulation of pre-synaptic vesicular glutamate transporter (VGlut) and increased spontaneous glutamate release. Increased lap expression reversed these phenotypes back to control levels, suggesting that lap may modulate glutamatergic transmission. We also found that lap modulated the localisation of Amph, the homologue of another AD risk factor BIN1, and that Amph itself modulated post-synaptic glutamate receptor (GluRII) localisation. We propose a model where PICALM modulates glutamatergic transmission, together with BIN1, to ameliorate synaptic dysfunction and disease progression.

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Neuronal BIN1 Regulates Presynaptic Neurotransmitter Release and Memory Consolidation

Cited by 71 publications

References 73 publications

Alzheimer’s disease risk geneBIN1induces Tau-dependent network hyperexcitability

Alzheimer’s disease risk geneBIN1induces Tau-dependent network hyperexcitability

Knockin’ on heaven’s door: Molecular mechanisms of neuronal tau uptake

PICALM rescues glutamatergic neurotransmission, behavioural function and survival in a Drosophila model of Aβ42 toxicity

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