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Micro RNA ‐125b induces tau hyperphosphorylation and cognitive deficits in Alzheimer's disease
Author(s) -
BanzhafStrathmann Julia,
Benito Eva,
May Stephanie,
Arzberger Thomas,
Tahirovic Sabina,
Kretzschmar Hans,
Fischer André,
Edbauer Dieter
Publication year - 2014
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201387576
Subject(s) - downregulation and upregulation , hyperphosphorylation , phosphorylation , gene knockdown , phosphatase , kinase , biology , cyclin dependent kinase 5 , microbiology and biotechnology , alzheimer's disease , cancer research , neuroscience , medicine , protein kinase a , apoptosis , biochemistry , disease , gene , mitogen activated protein kinase kinase
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 micro RNA ‐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 DUSP 6 and PPP 1 CA 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 PPP 1 CA 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, DUSP 6, and PPP 1 CA , resulting in increased tau phosphorylation in vivo . Importantly, DUSP 6 and PPP 1 CA are also reduced in AD brains. These data implicate miR‐125b in the pathogenesis of AD by promoting pathological tau phosphorylation.