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MicroRNA-125b induces tau hyperphosphorylation and cognitive deficits in Alzheimer's disease.


ABSTRACT: Sporadic Alzheimer's disease (AD) is the most prevalent form of dementia, but no clear disease-initiating mechanism is known. A? deposits and neuronal tangles composed of hyperphosphorylated tau are characteristic for AD. Here, we analyze the contribution of microRNA-125b (miR-125b), which is elevated in AD. In primary neurons, overexpression of miR-125b causes tau hyperphosphorylation and an upregulation of p35, cdk5, and p44/42-MAPK signaling. In parallel, the phosphatases DUSP6 and PPP1CA and the anti-apoptotic factor Bcl-W are downregulated as direct targets of miR-125b. Knockdown of these phosphatases induces tau hyperphosphorylation, and overexpression of PPP1CA and Bcl-W prevents miR-125b-induced tau phosphorylation, suggesting that they mediate the effects of miR-125b on tau. Conversely, suppression of miR-125b in neurons by tough decoys reduces tau phosphorylation and kinase expression/activity. Injecting miR-125b into the hippocampus of mice impairs associative learning and is accompanied by downregulation of Bcl-W, DUSP6, and PPP1CA, resulting in increased tau phosphorylation in vivo. Importantly, DUSP6 and PPP1CA are also reduced in AD brains. These data implicate miR-125b in the pathogenesis of AD by promoting pathological tau phosphorylation.

SUBMITTER: Banzhaf-Strathmann J 

PROVIDER: S-EPMC4194100 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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MicroRNA-125b induces tau hyperphosphorylation and cognitive deficits in Alzheimer's disease.

Banzhaf-Strathmann Julia J   Benito Eva E   May Stephanie S   Arzberger Thomas T   Tahirovic Sabina S   Kretzschmar Hans H   Fischer André A   Edbauer Dieter D  

The EMBO journal 20140707 15


Sporadic Alzheimer's disease (AD) is the most prevalent form of dementia, but no clear disease-initiating mechanism is known. Aβ deposits and neuronal tangles composed of hyperphosphorylated tau are characteristic for AD. Here, we analyze the contribution of microRNA-125b (miR-125b), which is elevated in AD. In primary neurons, overexpression of miR-125b causes tau hyperphosphorylation and an upregulation of p35, cdk5, and p44/42-MAPK signaling. In parallel, the phosphatases DUSP6 and PPP1CA and  ...[more]

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