Page 13 - IBRO_RNA School_Abstract Book

Rheb-mTOR Activation Rescues Amyloid Beta-Induced
Cognitive Impairment and Memory Function by Restoring

miRNA Activity in Glial Cells

Suvendra N. Bhattacharyya
CSIR-Indian Institute of Chemical Biology, Kolkata,

West Bengal, India

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 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 microRNPs in diseased brain. Exploring the mechanism of amyloid
beta induced cytokine expression, we have identified how the inactivation of

the repressive miR-146 microRNPs 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
mTORC1 complex to early endosomes that results in decreased Ago2
phosphorylation, limited Ago2-miRNA uncoupling and retarded Ago2-cytokine
mRNA interaction in rat astrocyte cells. Interestingly, constitutive activation
of mTORC1 by Rheb activator restricts proinflammatory cytokine production
by reactivating miR-146 microRNPs in amyloid beta exposed glial cells to rescue
the disease phenotype in the in vivo rat model of Alzheimer’s disease.