TITLE:
The interrelationship between insulin resistane and Alzheimer development
AUTHORS:
Doaa A. Ghareeb, Shimaa Mohamed, Mohamed El-Sayed
KEYWORDS:
Insulin Resistance; B-Amyloid; Oxidative Stress; Brain Inflammation
JOURNAL NAME:
Journal of Biomedical Science and Engineering,
Vol.6 No.7,
July
18,
2013
ABSTRACT:
Abnormalities
in insulin metabolism, characteristic of T2DM, are among the major factors
thought to mechanistically influence the onset of AD. These abnormalities
are thought to play a role in AD via their influence on the synthesis and
degradation of Aβ and as a
consequence of the cascade of neuronal alterations resulting from the effects
of danger/alarm signals from oligomeric amyloid species. Additionally, recent
studies have indicated that certain signal transduction pathways downstream of
the InsR may also promote the generation of Aβ peptides by modulating the cleavage of the parent Aβ precursor protein (AβPP) at the γ-secretase site, a cleavage site necessary for Aβ amyloidogenicity. Glucose homeostasis
is critical for energy generation, neuronal maintenance, neurogenesis, neurotransmitter
regulation, cell survival and synaptic plasticity. It also plays a key role
in cognitive function. In an insulin resistance condition, there is a reduced
sensitivity to insulin resulting in hyperinsulinemia; this condition persists
for several years before becoming full blown diabetes. Toxic levels of
insulin negatively influence neuronal function and survival, and elevation of
peripheral insulin concentration acutely increases its cerebrospinal fluid (CSF) concentration. Peripheral hyperinsulinemia correlates with an abnormal removal of the amyloid beta peptide (Aβ) and an increase of tau hyperphosphorylation
as a result of augmented cdk5 and GSK3β activities. This leads to cellular cascades that trigger a neurodegenerative
phenotype and decline in cognitive function. Chronic peripheral
hyperinsulinemia results in a reduction of insulin transport across the BBB
and reduced insulin signaling in brain, altering all of insulin’s actions,
including its anti-apoptotic effect. However, the increase in brain insulin
levels resulting from its peripheral administration at optimal doses has
shown a cognition enhancing effect on patient with AD.