Title

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

Journal

The EMBO journal

Volume

33

Issue

None

Pages

1667-80

Date

2014-08-01

Authors

Arzberger T | Banzhaf-Strathmann J | Benito E | Edbauer D | Fischer A | Kretzschmar H | May S | Tahirovic S

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.

Since Erk1/2 activity has been shown to induce cdk5 (Harada et al, 2001), miR-125b-induced Erk1/2 activation through DUSP6 downregulation might ultimately stimulate aberrant cdk5/p35 activation and, consequently, enhance pathological tau phosphorylation at multiple sites

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