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

作者：Banzhaf Strathmann Julia^*; Benito Eva; May Stephanie; Arzberger Thomas; Tahirovic Sabina; Kretzschmar Hans; Fischer Andre; Edbauer Dieter

来源：The EMBO Journal, 2014, 33(15): 1667-1680.

DOI：10.15252/embj.201387576

• Alzheimer's disease
• kinases
• microRNA-125b
• phosphatases
• tau phosphorylation

Sporadic Alzheimer's disease (AD) is the most prevalent form of dementia, but no clear disease-initiating mechanism is known. Ab 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.

• 出版日期2014-8-1