Title:Insulin Resistance in Alzheimer Disease: p53 and MicroRNAs as Important Players
Volume: 17
Issue: 12
Author(s): Kazimierz Gasiorowski, Barbara Brokos, Jerzy Leszek, Vadim V. Tarasov, Ghulam Md Ashraf and Gjumrakch Aliev
Affiliation:
Keywords:
Alzheimer disease, Insulin resistance, microRNAs, p53 protein, ROS.
Abstract: Glucose homeostasis is crucial for neuronal survival, synaptic plasticity, and is indispensable
for learning and memory. Reduced sensitivity of cells to insulin and impaired insulin signaling in
brain neurons participate in the pathogenesis of Alzheimer disease (AD). The tumor suppressor protein
p53 coordinates with multiple cellular pathways in response to DNA damage and cellular
stresses. However, prolonged stress conditions unveil deleterious effects of p53-evoked insulin resistance
in neurons; enhancement of transcription of pro-oxidant factors, accumulation of toxic metabolites
(e.g. ceramide and products of advanced glycation) and ROS-modified cellular components, together
with the activation of proapoptotic genes, could finally induce a suicide death program of
autophagy/apoptosis in neurons. Recent studies reveal the impact of p53 on expression and processing
of several microRNAs (miRs) under DNA damage-inducing conditions. Additionally, the role of
miRs in promotion of insulin resistance and type 2 diabetes mellitus has been well documented. Detailed
recognition of the role of p53/miRs crosstalk in driving insulin resistance in AD brains could
improve the disease diagnostics and aid future therapy.
