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

• DOI: 10.15252/embj.201387576
• Publication Date: 2014-07-08T03:29:26Z
• Authors: Julia Banzhaf‐Str...; Eva Benito; Stephanie May; Thomas Arzberger; Sabina Tahirovic; Hans Kretzschmar; André Fischer; Dieter Edbauer
• Keywords: 0301 basic medicine; metabolism [Apoptosis Regulatory Proteins]; drug effects [Hippocampus]; DUSP6 protein, human; Down-Regulation; genetics [Alzheimer Disease]; metabolism [Hippocampus]; MAPT protein, human; tau Proteins; metabolism [Protein Phosphatase 1]; genetics [Cognition Disorders]; Hippocampus; Gene Knockout Techniques; Mice; 03 medical and health sciences; metabolism [MicroRNAs]; Alzheimer Disease; Dual Specificity Phosphatase 6; Memory; ddc:570; Protein Phosphatase 1; Animals; Humans; genetics [MicroRNAs]; pharmacology [MicroRNAs]; genetics [Protein Phosphatase 1]; Phosphorylation; physiology [Memory]; Cells, Cultured; Neurons; PPP1CA protein, human; genetics [Dual Specificity Phosphatase 6]; MIRN125 microRNA, human; metabolism [tau Proteins]; BCL2L2 protein, human; 3. Good health; genetics [Apoptosis Regulatory Proteins]; Mice, Inbred C57BL; MicroRNAs; metabolism [Neurons]; Apoptosis Regulatory Proteins; Cognition Disorders; metabolism [Dual Specificity Phosphatase 6]; metabolism [Alzheimer Disease]

AbstractSporadic 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 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.