Loss of Bin1 Promotes the Propagation of Tau Pathology

Calafate, Sara; Flavin, William P.; Verstreken, Patrik; Moechars, Diederik

doi:10.1016/j.celrep.2016.09.063

Cited by 207 publications

(243 citation statements)

References 46 publications

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“…Previously reported effects of experimentally altered BIN1 expression on Tau pathology have been controversial too. While loss of BIN1 was shown to reduce Tau mediated neurodegeneration in Drosophila [42], it reduced the propagation of Tau pathology in an in vitro system [44]. We did not observe a significant effect of BIN1 downregulation on wildtype total Tau or pTau(Thr231) levels in our study.…”

Section: Resultscontrasting

confidence: 70%

Analysis of Aβx-42/Aβx-40 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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Section: Resultscontrasting

confidence: 70%

Analysis of Aβx-42/Aβx-40 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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“…Besides mediating synaptic toxicity and exosomal spread of disease, we briefly note that some studies have linked retromer trafficking (Small and Petsko, 2015), BIN1 (Calafate et al, 2016; Chapuis et al, 2013; Zhou et al, 2014), and CD2AP (Shulman et al, 2014) to tau pathology, potentially independent of amyloid, and retromer has also been linked to immune response genes, such as TREM2, that are phagocytic receptors trafficked in microglia (Lucin et al, 2013; Small and Petsko, 2015; Sole-Domenech et al, 2016; Yin et al, 2016). A detailed discussion of these additional pathophysiological links is considered outside the scope of this Opinion.…”

Section: Endosomal Traffic Jams and Downstream Pathophysiologymentioning

confidence: 99%

Endosomal Traffic Jams Represent a Pathogenic Hub and Therapeutic Target in Alzheimer’s Disease

Small

Simoes-Spassov

Mayeux

et al. 2017

Trends in Neurosciences

125

111

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While clues have existed that endosomal trafficking is associated with Alzheimer’s disease (AD), whether it plays a central role in the disease and if so how has remained unknown. Here we rely on recent genetic and cellular findings to construct a model proposing that traffic jams in the early endosome can act as an upstream pathogenic hub in AD. We also rely on an independent series of findings to suggest how the traffic jams can act as a unified mediator of downstream pathophysiology. The model predicts, therefore, that interventions designed to unjam the endosome carry high therapeutic promise.

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“…BIN1 is a widely expressed adapter protein that functions in clathrin-mediated endocytosis and endocytic recycling, leading some researchers to believe that BIN1 , in turn, functions in AβPP metabolism (34). BIN1 is also involved in the regulation of cytoskeleton dynamics, where the tubular membrane structures it forms appear to link the microtubule skeleton with the cellular membrane, leading others to believe that it modulates tau pathology (35, 36). PICALM is another widely expressed gene that encodes an adapter protein that functions in clathrin-mediated endocytosis and endocytic recycling, whose polymorphic variants rs3851179 and rs10792832 have also been associated with AD in GWAS studies (32, 37, 38).…”

Section: Other Potential Genetic Biomarkersmentioning

confidence: 99%

Alzheimer’s Disease: Biomarkers in the Genome, Blood, and Cerebrospinal Fluid

Huynh

Mohan

2017

Front. Neurol.

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that slowly destroys memory and thinking skills, resulting in behavioral changes. It is estimated that nearly 36 million are affected globally with numbers reaching 115 million by 2050. AD can only be definitively diagnosed at autopsy since its manifestations of senile plaques and neurofibrillary tangles throughout the brain cannot yet be fully captured with current imaging technologies. Current AD therapeutics have also been suboptimal. Besides identifying markers that distinguish AD from controls, there has been a recent drive to identify better biomarkers that can predict the rates of cognitive decline and neocortical amyloid burden in those who exhibit preclinical, prodromal, or clinical AD. This review covers biomarkers of three main types: genes, cerebrospinal fluid-derived, and blood-derived biomarkers. Looking ahead, cutting-edge OMICs technologies, including proteomics and metabolomics, ought to be fully tapped in order to mine even better biomarkers for AD that are more predictive.

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Loss of Bin1 Promotes the Propagation of Tau Pathology

Cited by 207 publications

References 46 publications

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

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

Endosomal Traffic Jams Represent a Pathogenic Hub and Therapeutic Target in Alzheimer’s Disease

Alzheimer’s Disease: Biomarkers in the Genome, Blood, and Cerebrospinal Fluid

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