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

• Published in: The EMBO journal 2014-08, Vol.33 (15), p.1667-1680
• Main Authors: Banzhaf-Strathmann, Julia, Benito, Eva, May, Stephanie, Arzberger, Thomas, Tahirovic, Sabina, Kretzschmar, Hans, Fischer, André, Edbauer, Dieter
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Animals; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Cells, Cultured; Cognition Disorders - genetics; Dementia disorders; Down-Regulation; Dual Specificity Phosphatase 6 - genetics; Dual Specificity Phosphatase 6 - metabolism; EMBO27; Gene Knockout Techniques; Hippocampus - drug effects; Hippocampus - metabolism; Humans; kinases; Memory - physiology; Mice; Mice, Inbred C57BL; microRNA-125b; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; MicroRNAs - pharmacology; Neurons - metabolism; Phosphatase; phosphatases; Phosphorylation; Protein Phosphatase 1 - genetics; Protein Phosphatase 1 - metabolism; tau phosphorylation; tau Proteins - metabolism
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.201387576

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 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. Synopsis Altered microRNA expression has been described for brains from Alzheimer's disease (AD) patients. This study links upregulation of miR‐125b to enhanced tau phosphorylation in primary neurons and mouse brains, subsequently leading to impaired learning and memory, both hallmarks of AD. miR‐125b is elevated in the frontal cortex of AD patients. miR‐125b overexpression induces tau phosphorylation at multiple sites. miR‐125b blocks the expression of the phosphatases DUSP6 and PPP1CA as well as the anti‐apoptotic protein Bcl‐W. Repression of these miR‐125b targets activates the tau kinases cdk5/p35 and Erk1/2. Injection of miR‐125b into the dentate gyrus of wild‐type mice impairs learning and memory. Graphical Abstract Direct regulation of tau kinases and phosphatases by an Alzheimer's disease‐overexpressed miRNA promotes pathological tau phosphorylation and accompanying learning and memory defects.