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5. Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer's disease.
This study was
first published on-line on March 19, 2004.
"Recent epidemiological evidence indicates that insulin resistance, a
proximal cause of Type II diabetes [a non-insulin dependent form of
diabetes mellitus (NIDDM)], is associated with an increased relative
risk for Alzheimer's disease (AD). In this study we examined the role
of dietary conditions leading to NIDDM-like insulin resistance on
amyloidosis in Tg2576 mice, which model AD-like neuropathology. We
found that diet-induced insulin resistance promoted amyloidogenic
beta-amyloid (Abeta) Abeta1-40 and Abeta1-42 peptide generation in the
brain that corresponded with increased gamma-secretase activities and
decreased insulin degrading enzyme (IDE) activities. Moreover,
increased Abeta production also coincided with increased AD-type
amyloid plaque burden in the brain and impaired performance in a
spatial water maze task. Further exploration of the apparent
interrelationship of insulin resistance to brain amyloidosis revealed
a functional decrease in insulin receptor (IR)-mediated signal
transduction in the brain, as suggested by decreased IR beta-subunit
(IRbeta) Y1162/1163 autophosphorylation and reduced
phosphatidylinositol 3 (PI3)-kinase/pS473-AKT/Protein kinase (PK)-B in
these same brain regions. This latter finding is of particular
interest given the known inhibitory role of AKT/PKB on glycogen
synthase kinase (GSK)-3alpha activity, which has previously been shown
to promote Abeta peptide generation. Most interestingly, we found that
decreased pS21-GSK-3alpha and pS9-GSK-3beta phosphorylation, which is
an index of GSK activation, positively correlated with the generation
of brain C-terminal fragment (CTF)-gamma cleavage product of amyloid
precursor protein, an index of gamma-secretase activity, in the brain
of insulin-resistant relative to normoglycemic Tg2576 mice. Our study
is consistent with the hypothesis that insulin resistance may be an
underlying mechanism responsible for the observed increased relative
risk for AD neuropathology, and presents the first evidence to suggest
that IR signaling can influence Abeta production in the brain." (12).
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