Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology

Chapuis, Julien; Hansmannel, Franck; Gistelinck, Marc; Mounier, Anaïs; Cauwenberghe, Caroline Van; Kolen, Kristof Van; Geller, Frank; Sottejeau, Yoann; Harold, Denise; Dourlen, Pierre; Grenier‐Boley, Benjamin; Kamatani, Yoichiro; Delepine, B; Demiautte, Florie; Zélénika, Diana; Zommer, Nadège; Hamdane, Malika; Bellenguez, Céline; Jf, Dartigues; Hauw, J J; Letronne, Florent; Ayral, Anne Marie; Sleegers, Kristel; Schellens, Ann; Broeck, Lies Vanden; Engelborghs, S.; Deyn, Peter Paul De; Vandenberghe, Rik; Mc, O’Donovan; Owen, Michael John; Epelbaum, Jacques; Mercken, Mark; Karran, Eric; Bantscheff, Marcus; Drewes, Gerard; Joberty, Gérard; Campion, Dominique; Octave, Jean Noël; Berr, Claudine; Lathrop, Mark; Callaerts, Patrick; Mann, David; Williams, Julie; Buée, Luc; Dewachter, Ilse; Broeckhoven, Christine Van; Amouyel, Philippe; Moechars, Dieder; Dermaut, Bart; Lambert, Jean‐Charles

doi:10.1038/mp.2013.1

Cited by 324 publications

(398 citation statements)

References 24 publications

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“…This might be related to the tau-binding property of ApoE (Fleming et al, 1996;Strittmatter et al, 1994). Unexpectedly, genes functionally connected to endocytic pathways and modification of tau pathology, such as BIN1 (Chapuis et al, 2013) and PICALM (Xiao et al, 2012), did not affect tau secretion or uptake significantly. Instead, CD2AP, FRMD4A, TREM2 and CD33 knockdown caused a significant decrease in tau secretion.…”

Section: Discussionmentioning

confidence: 89%

FRMD4A-cytohesin signaling modulates cellular release of Tau

Nykänen

Brunello

et al. 2016

Journal of Cell Science

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One of the defining pathological features of Alzheimer's disease is the intraneuronal accumulation of tau (also known as MAPT) protein.Tau is also secreted from neurons in response to various stimuli and accumulates in the cerebrospinal fluid of Alzheimer's disease patients. Tau pathology might spread from cell to cell through a mechanism involving secretion and uptake. Here, we developed an assay to follow cellular release and uptake of tau dimers. Individual silencing of ten common late-onset Alzheimer's disease risk genes in HEK293T cells expressing the tau reporters suggested that FRMD4A is functionally linked to tau secretion. FRMD4A depletion by using RNA interference (RNAi) reduced and overexpression increased tau secretion. The activity of cytohesins, interactors of FRMD4A and guanine-nucleotide-exchange factors of Arf6, was necessary for FRMD4A-induced tau secretion. Increased Arf6 and cell polarity signaling through Par6 and atypical protein kinase Cζ (aPKCζ) stimulated tau secretion. In mature cortical neurons, FRMD4A RNAi or inhibition of cytohesins strongly upregulated secretion of endogenous tau. These results suggest that FRMD4A, a genetic risk factor for late-onset Alzheimer's disease, regulates tau secretion by activating cytohesin-Arf6 signaling. We conclude that genetic risk factors of Alzheimer's disease might modulate disease progression by altering tau secretion.

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Section: Discussionmentioning

confidence: 89%

FRMD4A-cytohesin signaling modulates cellular release of Tau

Nykänen

Brunello

et al. 2016

Journal of Cell Science

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“…It is important to stress that the rs744373 polymorphism is most likely a marker SNP that is in LD with one or more functional variations located elsewhere within BIN1 that also affects the current findings. Chapuis et al, (2013) reported that the SNP rs744373 was in almost complete LD (D' = 0.98, r 2 = 0.94) with the functional insertion/deletion rs59335482 in Caucasian populations. The functional rs59335482 insertion risk allele was found to be associated with an increase in BIN1 transcriptional activity in vitro, BIN1 expression levels in the human brain and AD risk.…”

Section: Discussionmentioning

confidence: 99%

“…The exact pathogenic mechanisms of BIN1 in the AD pathophysiological process remain to be determined. Emerging data suggest that BIN1 might modulate microtubule stability, Tau phosphorylation/aggregation, or neurofibrillary tangle formation (Chapuis et al, 2013). BIN1 has also been identified as a regulator of endocytosis and trafficking, immunity and inflammation of the brain, transient calcium potentials, and apoptosis (Lambert et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, the results of pooled analysis and meta-analysis indicated that the rs744373 polymorphism contributed to AD with similar genetic risk in East Asian and Caucasian populations (Liu et al, 2013). The SNP rs744373 is in almost complete linkage disequilibrium (LD) (D' = 0.98, r 2 = 0.94) with functional rs59335482, which is associated with an increase in BIN1 transcriptional activity (Chapuis et al, 2013). In the brains of patients with AD, BIN1 protein expression levels increase in several regions, especially the hippocampus, and are correlated with tau pathology (Holler et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Bridging Integrator 1 (BIN1) Genotype Effects on Working Memory, Hippocampal Volume, and Functional Connectivity in Young Healthy Individuals

Zhang

et al. 2015

Neuropsychopharmacol

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Alzheimer's disease (AD) is the most common form of dementia and exhibits a considerable level of heritability. The bridging integrator 1 (BIN1) gene has recently been identified in several large genome-wide association studies (GWAS) as the second most important risk locus for AD following apolipoprotein E (APOE). However, how and when the established genetic risk locus BIN1 rs744373 confers risk to late-onset AD has yet to be determined. Here using an imaging genetic strategy in large-sample Chinese subjects, we show that healthy homozygous carriers of the rs744373 risk allele exhibit worse high-load working memory (WM) performance, larger hippocampal volume and lower functional connectivity between the bilateral hippocampus and the right dorsolateral prefrontal cortex (DLPFC), mirroring clinical evidence of disturbed memory and connectivity in patients. Our findings demonstrate that rs744373 itself or a variation in linkage disequilibrium may provide a neurogenetic mechanism for BIN1 while further validating the possibility of combining genetic and neuroimaging strategies to monitor individuals at risk for AD.

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“…EOAD is caused by a specific set of highly penetrant mutations, which affect almost exclusively either the amyloid precursor protein (APP) or the catalytically active Presenilin subunit of the Aβ-producing γ-secretase complex. These mutations enhance the overall production of Aβ peptides and/or increase the ratio of the aggregation prone and neurotoxic Aβ 42 over the common, shorter Aβ 40 . The genetic contribution to LOAD, on the other hand, is not very well understood.…”

Section: Introductionmentioning

confidence: 99%

Analysis of Aβ<sub>x-42</sub>/Aβ<sub>x-40</sub> and Tau upon siRNA-mediated downregulation of APOE, BIN1, PICALM, CLU, PRNP and CST3 in wildtype mouse primary neurons

Siegel

Rajendran

2018

Matters

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Alzheimer's disease (AD) is the most common form of dementia in the elderly. It is a progressive neurodegenerative disorder that is characterized by the abundant presence of cerebral β-amyloid (Aβ) plaques and neurofibrillary Tau tangles. The rare, early-onset AD is caused by mutations mainly within either the amyloid precursor protein (APP) or Presenilins 1 or 2 (PS1 or PS2), the catalytic subunits of the γ-secretase complex. These mutations either increase overall Aβ production or specifically alter γ-secretase mediated processing towards an increased production ratio of Aβ 42 :Aβ 40 . For late-onset AD, however, which accounts for the vast majority of AD cases, the exact mechanisms by which the disease is caused are not known. While genome-wide association studies (GWAS) have identified certain genetic risk factors associated with late-onset AD, the mechanisms through which they contribute to the pathogenesis are still elusive. Previously, using a HeLa cell model of Aβ production, it was shown that, in contrast to the early-onset AD causing mutations, knockdown of late-onset AD susceptibility genes did not specifically affect the Aβ 42 :Aβ 40 ratio [1]. To validate these findings in a neuronal setting without any overexpression of APP, here we re-addressed the role of six late-onset AD risk genes (APOE, BIN1, PICALM, CLU, PRNP and CST3) in the regulation of γ-secretase mediated APP processing in wild-type mouse primary neurons by analyzing Aβ x-40 and Aβ x-42 . In addition, we extended the analysis by also including measurements of total Tau protein and phosphorylation of Tau at Threonine 231, a non-physiological phosphorylation site that is associated with AD. The siRNA-mediated knockdown of the studied LOAD risk genes neither affected the Aβ x-42 :Aβ x-40 ratio nor altered the levels of total Tau or phospho(Thr231)-Tau. Our results thus show that acute downregulation of these genes in wild-type mouse primary neurons does not significantly impact on γ-secretase mediated APP processing nor Tau homeostasis or Tau phosphorylation.

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Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology

Cited by 324 publications

References 24 publications

FRMD4A-cytohesin signaling modulates cellular release of Tau

FRMD4A-cytohesin signaling modulates cellular release of Tau

Bridging Integrator 1 (BIN1) Genotype Effects on Working Memory, Hippocampal Volume, and Functional Connectivity in Young Healthy Individuals

Analysis of Aβ<sub>x-42</sub>/Aβ<sub>x-40</sub> and Tau upon siRNA-mediated downregulation of APOE, BIN1, PICALM, CLU, PRNP and CST3 in wildtype mouse primary neurons

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