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

Abstract

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.

Compromised MAPK signaling in human diseases: an update

“…Specifically, overexpression of microRNA125b (miR-125b) is thought to result in tau hyperphosphorylation in neurons as a result of down-regulation of the phosphatases DUSP6 and PPP1CA, transcripts for both of which are direct targets of miR-125b (Banzhaf-Strathmann et al 2014). In this case, the phosphatases DUSP6 and PPP1CA, which are direct substrates of miR-125b, are also down-regulated in neurons, which induce tau hyperphosphorylation (Banzhaf-Strathmann et al 2014). Oxidative stress is a key risk factor for the pathogenesis of AD (Pratico 2008).…”

Molecular and cellular pathophysiology of preclinical Alzheimer’s disease

“…Various miRNAs regulate a multitude of brain functions (e.g., synaptic plasticity and energy metabolism) [101-104] suggesting that perturbations in miRNA function is involved in the pathogenesis of complex neurodegenerative disorders including AD [99, 100]. AD brains display altered expression of miRNAs that regulate BACE1 enzyme [105, 106] and are linked to tau phosphorylation [107-109] and pro-inflammatory actions [107, 110-112]. The role that the dysregulation of brain miRNA networks play early in AD are unclear.…”

MicroRNA-613 regulates the expression of brain-derived neurotrophic factor in Alzheimer's disease

“…Recently, several miRNAs have been found to be related to AD pathogenesis by affecting the expression of function of AD-relevant molecules such as amyloid precursor protein (APP) (7), β-site amyloid precursor protein cleaving enzyme 1 (BACE1) (8) or Tau (9,10). Measurements of miRNAs in blood and cerebrospinal fluid (CSF) have become a novel diagnostic tool for various neurological diseases, including AD.…”