Dataset Information

Stabilization of dynamic microtubules by mDia1 drives Tau-dependent A?_1-42 synaptotoxicity.

ABSTRACT: Oligomeric Amyloid ?_1-42 (A?) plays a crucial synaptotoxic role in Alzheimer's disease, and hyperphosphorylated tau facilitates A? toxicity. The link between A? and tau, however, remains controversial. In this study, we find that in hippocampal neurons, A? acutely induces tubulin posttranslational modifications (PTMs) and stabilizes dynamic microtubules (MTs) by reducing their catastrophe frequency. Silencing or acute inhibition of the formin mDia1 suppresses these activities and corrects the synaptotoxicity and deficits of axonal transport induced by A?. We explored the mechanism of rescue and found that stabilization of dynamic MTs promotes tau-dependent loss of dendritic spines and tau hyperphosphorylation. Collectively, these results uncover a novel role for mDia1 in A?-mediated synaptotoxicity and demonstrate that inhibition of MT dynamics and accumulation of PTMs are driving factors for the induction of tau-mediated neuronal damage.

SUBMITTER: Qu X

PROVIDER: S-EPMC5626542 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Stabilization of dynamic microtubules by mDia1 drives Tau-dependent Aβ<sub>1-42</sub> synaptotoxicity.

Qu Xiaoyi X Yuan Feng Ning FN Corona Carlo C Pasini Silvia S Pero Maria Elena ME Gundersen Gregg G GG Shelanski Michael L ML Bartolini Francesca F

The Journal of cell biology 20170906 10

Oligomeric Amyloid β<sub>1-42</sub> (Aβ) plays a crucial synaptotoxic role in Alzheimer's disease, and hyperphosphorylated tau facilitates Aβ toxicity. The link between Aβ and tau, however, remains controversial. In this study, we find that in hippocampal neurons, Aβ acutely induces tubulin posttranslational modifications (PTMs) and stabilizes dynamic microtubules (MTs) by reducing their catastrophe frequency. Silencing or acute inhibition of the formin mDia1 suppresses these activities and corr ...[more]

PMID: 28877993

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Project description:Amyloid beta (Abeta) 1-42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI) and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer's disease (AD). We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1) protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90%. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimer's disease patients' brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological effects of Abeta oligomers in AD and is a tractable target for small molecule disease-modifying therapeutics.

Dataset Information

Stabilization of dynamic microtubules by mDia1 drives Tau-dependent A?1-42 synaptotoxicity.

Publications

Stabilization of dynamic microtubules by mDia1 drives Tau-dependent Aβ<sub>1-42</sub> synaptotoxicity.

Similar Datasets

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Stabilization of dynamic microtubules by mDia1 drives Tau-dependent A?_1-42 synaptotoxicity.