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. 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.
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HT22 cells may be suitable for analysing neuronal apoptosis regulated by miRNAs.
“Since both miRNAs are involved in regulating processes of neuronal death [52–55], HT22 cells may be suitable for analysing neuronal apoptosis regulated by miRNAs.”
From Shared and distinct microRNA profiles between HT22, N2A and SH-SY5Y cell lines and primary mouse hippocampal neurons (2025) · cites this paper as [53]
MiR-125b is highly elevated and pathogenic in the AD brain, promoting tau hyperphosphorylation and apoptotic signaling by suppressing phosphatases such as DUSP6 and PPP1CA.
“MiR-125b is highly elevated and pathogenic in the AD brain, promoting tau hyperphosphorylation and apoptotic signaling by suppressing phosphatases such as DUSP6 and PPP1CA (Banzhaf-Strathmann et al., 2014).”
From Cell-specific MicroRNA networks orchestrate the pathogenesis of Alzheimer’s disease (2026) · cites this paper as Banzhaf-Strathmann et al., 2014
MiR-34a/c promotes apoptosis and impairs synaptic plasticity; their inhibition rescues memory in AD mouse models.
“MiR-34a/c also promotes apoptosis and impair synaptic plasticity; their inhibition rescues memory in AD mouse models (Banzhaf-Strathmann et al., 2014; Sarkar et al., 2016; Zovoilis et al., 2011).”
From Cell-specific MicroRNA networks orchestrate the pathogenesis of Alzheimer’s disease (2026) · cites this paper as Banzhaf-Strathmann et al., 2014
Inhibiting miR-21-5p reduces gliosis and protects neuronal integrity.
“Inhibiting miR-21-5p reduces gliosis and protects neuronal integrity, making it a prime candidate for astrocyte-based therapeutic strategies (Banzhaf-Strathmann et al., 2014; Garcia et al., 2022; Wang et al., 2008).”
From Cell-specific MicroRNA networks orchestrate the pathogenesis of Alzheimer’s disease (2026) · cites this paper as Banzhaf-Strathmann et al., 2014
Elevated levels of miR-206, miR-34a, miR-125b, and let-7b in plasma or CSF reflect trophic withdrawal, apoptosis, and innate immune activation.
“Elevated levels of miR-206, miR-34a, miR-125b, and let-7b in plasma or CSF reflect trophic withdrawal, apoptosis, and innate immune activation, highlighting their pathogenic roles in neuronal and glial cells, though cohort replication varies (Banzhaf-Strathmann et al., 2014; Lee et al., 2012; Lehmann et al., 2012; Riancho et al., 2017; Sarkar et al., 2016; Tian et al., 2014).”
From Cell-specific MicroRNA networks orchestrate the pathogenesis of Alzheimer’s disease (2026) · cites this paper as Banzhaf-Strathmann et al., 2014
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- Authors
- Banzhaf‐Strathmann, J., Benito, E., May, S., Arzberger, T., Tahirovic, S., Kretzschmar, H., Fischer, A., & Edbauer, D.
- Venue
- The EMBO Journal
- Published
- 2014-07-07
- Volume
- 33
- Issue
- 15
- Pages
- 1667-1680
- ISSN
- 0261-4189
- 1460-2075
- Cited by
- 326
- References
- 14
- Language
- en
- Funders
- Helmholtz Young Investigator program (HZ‐NG‐607)
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