MicroRNA-132 provides neuroprotection for tauopathies via multiple signaling pathways
Rachid El Fatimy1, Shaomin Li2, Zhicheng Chen2
1Department of Neurology, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, 60 Fenwood Rd, 9006, Boston, MA, 02115, USA. relfatimy@bwh.harvard.edu.
Abstract:
MicroRNAs (miRNA) regulate fundamental biological processes, including neuronal plasticity, stress response, and survival. Here, we describe a neuroprotective function of miR-132, the miRNA most significantly downregulated in neurons in Alzheimer's disease. We demonstrate that miR-132 protects primary mouse and human wild-type neurons and more vulnerable Tau-mutant neurons against amyloid β-peptide (Aβ) and glutamate excitotoxicity. It lowers the levels of total, phosphorylated, acetylated, and cleaved forms of Tau implicated in tauopathies, promotes neurite elongation and branching, and reduces neuronal death. Similarly, miR-132 attenuates PHF-Tau pathology and neurodegeneration, and enhances long-term potentiation in the P301S Tau transgenic mice. The neuroprotective effects are mediated by direct regulation of the Tau modifiers acetyltransferase EP300, kinase GSK3β, RNA-binding protein Rbfox1, and proteases Calpain 2 and Caspases 3/7. These data suggest miR-132 as a master regulator of neuronal health and indicate that miR-132 supplementation could be of therapeutic benefit for the treatment of Tau-associated neurodegenerative disorders.
Insights
MicroRNA-132 (miR-132) protects neurons against Alzheimer's disease toxins. Supplementing miR-132 may offer a therapeutic strategy for tauopathies and neurodegenerative disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- MicroRNAs (miRNAs) are crucial regulators of biological processes, including neuronal function.
- Alzheimer's disease is characterized by the downregulation of miR-132 in neurons.
- Tau pathology is a hallmark of tauopathies and neurodegenerative diseases.
Purpose of the Study:
- To investigate the neuroprotective role of miR-132 in Alzheimer's disease models.
- To elucidate the molecular mechanisms underlying miR-132's protective effects against tau pathology and excitotoxicity.
Main Methods:
- Primary neuronal cultures (mouse and human) and P301S Tau transgenic mice were used.
- Neuronal viability, neurite outgrowth, and long-term potentiation were assessed.
- Levels of total, phosphorylated, acetylated, and cleaved Tau were measured.
- Direct targets of miR-132, including EP300, GSK3β, Rbfox1, Calpain 2, and Caspases 3/7, were identified.
Main Results:
- miR-132 demonstrated significant neuroprotection against amyloid β-peptide and glutamate excitotoxicity in both wild-type and Tau-mutant neurons.
- miR-132 reduced various forms of Tau, promoted neurite elongation and branching, and decreased neuronal death.
- In vivo studies showed that miR-132 attenuated PHF-Tau pathology, neurodegeneration, and enhanced long-term potentiation.
- miR-132 directly regulates key Tau modifiers and proteases involved in neurodegeneration.
Conclusions:
- miR-132 acts as a master regulator of neuronal health and possesses potent neuroprotective properties.
- miR-132 supplementation presents a promising therapeutic avenue for tau-associated neurodegenerative disorders.
- Targeting miR-132 pathways could be a novel strategy for treating Alzheimer's disease and related conditions.
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