Alzheimer’s disease risk gene BIN1 induces Tau-dependent network hyperexcitability

Voskobiynyk, Yuliya; Roth, Jonathan R.; Cochran, J. Nicholas; Rush, Travis; Carullo, Nancy V.N.; Mesina, Jacob S; Waqas, Mohammad; Vollmer, Rachael M; Day, Jeremy J.; McMahon, Lori L.; Roberson, Erik D.

doi:10.7554/elife.57354

Cited by 44 publications

(26 citation statements)

References 88 publications

(113 reference statements)

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“…Overall, BIN1 knockout leads to deficits in synaptic transmission, and impaired spatial memory consolidation at the behavioural level [381]. Tau reduction has also been shown to reduce network hyperexcitability mediated by BIN1-interactions with L-type voltage-gated calcium channels (LVGCCs) [458]. BIN1 can rearrange the actin cytoskeleton and stabilise Tau-induced actin bundles [108].…”

Section: Bin1 Rin3 and Cd2apmentioning

confidence: 99%

Synaptic tau: A pathological or physiological phenomenon?

Robbins

Clayton

Schierle

2021

acta neuropathol commun

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In this review, we discuss the synaptic aspects of Tau pathology occurring during Alzheimer’s disease (AD) and how this may relate to memory impairment, a major hallmark of AD. Whilst the clinical diagnosis of AD patients is a loss of working memory and long-term declarative memory, the histological diagnosis is the presence of neurofibrillary tangles of hyperphosphorylated Tau and Amyloid-beta plaques. Tau pathology spreads through synaptically connected neurons to impair synaptic function preceding the formation of neurofibrillary tangles, synaptic loss, axonal retraction and cell death. Alongside synaptic pathology, recent data suggest that Tau has physiological roles in the pre- or post- synaptic compartments. Thus, we have seen a shift in the research focus from Tau as a microtubule-stabilising protein in axons, to Tau as a synaptic protein with roles in accelerating spine formation, dendritic elongation, and in synaptic plasticity coordinating memory pathways. We collate here the myriad of emerging interactions and physiological roles of synaptic Tau, and discuss the current evidence that synaptic Tau contributes to pathology in AD.

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Section: Bin1 Rin3 and Cd2apmentioning

confidence: 99%

Synaptic tau: A pathological or physiological phenomenon?

Robbins

Clayton

Schierle

2021

acta neuropathol commun

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“…However, most of previous evidence showed an increase of BIN1 expression level in the brains of patients with AD [29,30]. Moreover, the increased BIN1 expression level has also been linked to tau pathology [29][30][31][32]. These inconsistent findings might be interpreted by the different functions of different domains in BIN1 gene.…”

Section: Discussionmentioning

confidence: 95%

Convergent lines of evidence support BIN1 as a risk gene of Alzheimer’s disease

Liu¹,

Yin

Gao

et al. 2021

Hum Genomics

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Genome-wide association studies (GWAS) have identified several susceptibility loci of Alzheimer’s disease (AD), which were mainly located in noncoding regions of the genome. Meanwhile, the putative biological mechanisms underlying AD susceptibility loci were still unclear. At present, identifying the functional variants of AD pathogenesis remains a major challenge. Herein, we first used summary data-based Mendelian randomization (SMR) with AD GWAS summary and expression quantitative trait loci (eQTL) data to identify variants who affects expression levels of nearby genes and contributed to the risk of AD. Using the SMR integrative analysis, we totally identified 14 SNPs significantly affected the expression level of 16 nearby genes in blood or brain tissues and contributed to the AD risk. Then, to confirm the results, we replicated the GWAS and eQTL results across multiple samples. Totally, four risk SNP (rs11682128, rs601945, rs3935067, and rs679515) were validated to be associated with AD and affected the expression level of nearby genes (BIN1, HLA-DRA, EPHA1-AS1, and CR1). Besides, our differential expression analysis showed that the BIN1 gene was significantly downregulated in the hippocampus (P = 2.0 × 10−3) and survived after multiple comparisons. These convergent lines of evidence suggest that the BIN1 gene identified by SMR has potential roles in the pathogenesis of AD. Further investigation of the roles of the BIN1 gene in the pathogenesis of AD is warranted.

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“…The tau mutation V337M linked to frontotemporal dementia was reported to increase neuronal activity by altering the axonal initial segment plasticity ( 121 ). Bin1, a protein involved in AD pathogenesis, was shown to regulate tau-dependent hyperexcitability in hippocampal neurons ( 122 ). Lastly, two tau mutations, Δ280 and A152T, were reported to induce hypoexcitability and hyperexcitability, respectively, in neuronal cultures ( 123 ).…”

Section: Section (Ii) Comparison Of the Pattern Of Tau Hyperphosphorymentioning

confidence: 99%

Similarities and Differences in the Pattern of Tau Hyperphosphorylation in Physiological and Pathological Conditions: Impacts on the Elaboration of Therapies to Prevent Tau Pathology

et al. 2021

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Tau protein, a neuronal microtubule-associated protein, becomes hyperphosphorylated in several neurodegenerative diseases called tauopathies. Hyperphosphorylation of tau is correlated to its redistribution from the axon to the somato-dendritic compartment at early stages of tauopathies. Interestingly, tau hyperphosphorylation begins in different regions of the brain in each tauopathy. In some regions, both neurons and glial cells develop tau hyperphosphorylation. Tau hyperphosphorylation is also observed in physiological conditions such as hibernation and brain development. In the first section of present article, we will review the spatiotemporal and cellular distribution of hyperphosphorylated tau in the most frequent tauopathies. In the second section, we will compare the pattern of tau hyperphosphorylation in physiological and pathological conditions and discuss the sites that could play a pivotal role in the conversion of non-toxic to toxic forms of hyperphosphorylated tau. Furthermore, we will discuss the role of hyperphosphorylated tau in physiological and pathological conditions and the fact that tau hyperphosphorylation is reversible in physiological conditions but not in a pathological ones. In the third section, we will speculate how the differences and similarities between hyperphosphorylated tau in physiological and pathological conditions could impact the elaboration of therapies to prevent tau pathology. In the fourth section, the different therapeutic approaches using tau as a direct or indirect therapeutic target will be presented.

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Alzheimer’s disease risk gene BIN1 induces Tau-dependent network hyperexcitability

Cited by 44 publications

References 88 publications

Synaptic tau: A pathological or physiological phenomenon?

Synaptic tau: A pathological or physiological phenomenon?

Convergent lines of evidence support BIN1 as a risk gene of Alzheimer’s disease

Similarities and Differences in the Pattern of Tau Hyperphosphorylation in Physiological and Pathological Conditions: Impacts on the Elaboration of Therapies to Prevent Tau Pathology

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