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:Alzheimer's disease (AD), the most common chronic neurodegenerative disorder, has complex neuropathology. The principal neuropathological hallmarks of the disease are the deposition of extracellular β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) comprised of hyperphosphorylated tau (p-tau) protein. These changes occur with neuroinflammation, a compromised blood-brain barrier (BBB) integrity, and neuronal synaptic dysfunction, all of which ultimately lead to neuronal cell loss and cognitive deficits in AD. Aβ1-42 was stereotaxically administered bilaterally into the CA1 region of the hippocampi of 18-month-old male C57BL/6 mice. This study aimed to characterize, utilizing immunohistochemistry and behavioral testing, the spatial and temporal effects of Aβ1-42 on a broad set of parameters characteristic of AD: p-tau, neuroinflammation, vascular pathology, pyramidal cell survival, and behavior. Three days after Aβ1-42 injection and before significant neuronal cell loss was detected, acute neuroinflammatory and vascular responses were observed. These responses included the up-regulation of glial fibrillary acidic protein (GFAP), cell adhesion molecule-1 (PECAM-1, also known as CD31), fibrinogen labeling, and an increased number of activated astrocytes and microglia in the CA1 region of the hippocampus. From day 7, there was significant pyramidal cell loss in the CA1 region of the hippocampus, and by 30 days, significant localized up-regulation of p-tau, GFAP, Iba-1, CD31, and alpha-smooth muscle actin (α-SMA) in the Aβ1-42-injected mice compared with controls. These molecular changes in Aβ1-42-injected mice were accompanied by cognitive deterioration, as demonstrated by long-term spatial memory impairment. This study is reporting a comprehensive examination of a complex set of parameters associated with intrahippocampal administration of Aβ1-42 in mice, their spatiotemporal interactions and combined contribution to the disease progression. We show that a single Aβ injection can reproduce aspects of the inflammatory, vascular, and p-tau induced pathology occurring in the AD human brain that lead to cognitive deficits.

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.

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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

OmicsDI is part of the ELIXIR infrastructure

Tweets

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