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Rheb-mTOR activation rescues Aβ-induced cognitive impairment and memory function by restoring miR-146 activity in
Dipayan De1, Ishita Mukherjee2, Subhalakshmi Guha3
1RNA Biology Research Laboratory, Molecular Genetics Division, CSIR-Indian Institute of Chemical Biology, Kolkata 700032, India.
Abstract:
Deposition of amyloid beta plaques in adult rat or human brain is associated with increased production of proinflammatory cytokines by associated glial cells that are responsible for degeneration of the diseased tissue. The expression of these cytokines is usually under check and is controlled at the post-transcriptional level via several microRNAs. Computational analysis of gene expression profiles of cortical regions of Alzheimer's disease patients' brain suggests ineffective target cytokine mRNA suppression by existing micro-ribonucleoproteins (miRNPs) in diseased brain. Exploring the mechanism of amyloid beta-induced cytokine expression, we have identified how the inactivation of the repressive miR-146 miRNPs causes increased production of cytokines in amyloid beta-exposed glial cells. In exploration of the cause of miRNP inactivation, we have noted amyloid beta oligomer-induced sequestration of the mTORC1 complex to early endosomes that results in decreased Ago2 phosphorylation, limited Ago2-miRNA uncoupling, and retarded Ago2-cytokine mRNA interaction in rat astrocytes. Interestingly, constitutive activation of mTORC1 by Rheb activator restricts proinflammatory cytokine production by reactivating miR-146 miRNPs in amyloid beta-exposed glial cells to rescue the disease phenotype in the in vivo rat model of Alzheimer's disease.
Insights
Alzheimer's disease involves amyloid beta plaques that increase cytokine production. Reactivating miR-146 micro-ribonucleoproteins (miRNPs) by activating mTORC1 can reduce inflammation and rescue disease phenotypes in rats.
Area of Science:
- Neuroscience
- Molecular Biology
- Immunology
Background:
- Amyloid beta plaques in Alzheimer's disease (AD) correlate with glial cell-mediated inflammation.
- MicroRNAs (miRNAs) typically regulate cytokine production post-transcriptionally.
- AD brains show impaired miRNA-mediated suppression of cytokine mRNA.
Purpose of the Study:
- To investigate the mechanism of amyloid beta-induced cytokine overproduction in glial cells.
- To identify how micro-ribonucleoprotein (miRNP) inactivation contributes to AD pathogenesis.
- To explore therapeutic strategies targeting miRNP function in AD.
Main Methods:
- Computational analysis of gene expression profiles from AD patient brain tissue.
- In vitro studies using rat astrocytes exposed to amyloid beta.
- In vivo studies using an established rat model of Alzheimer's disease.
Main Results:
- Amyloid beta exposure inactivates miR-146 miRNPs, leading to increased cytokine production.
- Amyloid beta oligomers sequester mTORC1 to early endosomes, reducing Ago2 phosphorylation and miRNP function.
- Constitutive mTORC1 activation by Rheb activator restores miR-146 miRNPs and reduces inflammation in vivo.
Conclusions:
- miR-146 miRNP inactivation is a key mechanism in amyloid beta-induced glial inflammation in AD.
- Targeting mTORC1 signaling offers a potential therapeutic avenue for AD by restoring miRNP activity.
- Modulating miRNPs presents a promising strategy for rescuing AD-related phenotypes.
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