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.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder typified by profound synaptic loss, brain atrophy, and the presence of extracellular plaques composed of amyloid β-protein (Aβ), and intracellular neurofibrillary tangles (NFTs) formed by hyperphosphorylated Tau [3, 27]
MiR-132 overexpression enhanced long-term potentiation (LTP) in WT mice and rescued the impairment of LTP seen in PS19 mice. These results suggest that miR-132 replacement could provide neuroprotection and therapeutic value for Tau-associated neurodegenerative disorders, including AD and frontotemporal dementia (FTD)
Individual miRNAs were inhibited in mouse primary hippocampal and cortical neurons by specific locked nucleic acid (LNA)-based antisense oligonucleotide inhibitors
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder typified by profound synaptic loss, brain atrophy, and the presence of extracellular plaques composed of amyloid β-protein (Aβ), and intracellular neurofibrillary tangles (NFTs) formed by hyperphosphorylated Tau [3, 27]. MiRNAs are small regulatory molecules that post-transcriptionally repress gene expression and thereby regulate diverse biological processes, including neuronal differentiation, plasticity, survival, and regeneration [42]. MiRNAs are often considered as determinants of cell fate and are increasingly acknowledged as prime regulators involved in various brain pathologies ranging from neurodevelopmental disorders to brain tumors, to neurodegenerative diseases. Multiple lines of evidence suggest that miRNAs may contribute to the progression of neurodegenerative diseases, the complexity of miRNA regulation in targeting many genes and pathways simultaneously raised concerns about their therapeutic utility as targetable molecules
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