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The Effects of Peripheral and Central High Insulin on Brain Insulin Signaling and
Amyloid-? in Young and Old APP/PS1 Mice
#MMPMID27852778
Stanley M
; Macauley SL
; Caesar EE
; Koscal LJ
; Moritz W
; Robinson GO
; Roh J
; Keyser J
; Jiang H
; Holtzman DM
J Neurosci
2016[Nov]; 36
(46
): 11704-11715
PMID27852778
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Hyperinsulinemia is a risk factor for late-onset Alzheimer's disease (AD). In
vitro experiments describe potential connections between insulin, insulin
signaling, and amyloid-? (A?), but in vivo experiments are needed to validate
these relationships under physiological conditions. First, we performed
hyperinsulinemic-euglycemic clamps with concurrent hippocampal microdialysis in
young, awake, behaving APP(swe)/PS1(dE9) transgenic mice. Both a postprandial and
supraphysiological insulin clamp significantly increased interstitial fluid (ISF)
and plasma A? compared with controls. We could detect no increase in brain, ISF,
or CSF insulin or brain insulin signaling in response to peripheral
hyperinsulinemia, despite detecting increased signaling in the muscle. Next, we
delivered insulin directly into the hippocampus of young APP/PS1 mice via reverse
microdialysis. Brain tissue insulin and insulin signaling was dose-dependently
increased, but ISF A? was unchanged by central insulin administration. Finally,
to determine whether peripheral and central high insulin has differential effects
in the presence of significant amyloid pathology, we repeated these experiments
in older APP/PS1 mice with significant amyloid plaque burden. Postprandial
insulin clamps increased ISF and plasma A?, whereas direct delivery of insulin to
the hippocampus significantly increased tissue insulin and insulin signaling,
with no effect on A? in old mice. These results suggest that the brain is still
responsive to insulin in the presence of amyloid pathology but increased insulin
signaling does not acutely modulate A? in vivo before or after the onset of
amyloid pathology. Peripheral hyperinsulinemia modestly increases ISF and plasma
A? in young and old mice, independent of neuronal insulin signaling. SIGNIFICANCE
STATEMENT: The transportation of insulin from blood to brain is a saturable
process relevant to understanding the link between hyperinsulinemia and AD. In
vitro experiments have found direct connections between high insulin and
extracellular A?, but these mechanisms presume that peripheral high insulin
elevates brain insulin significantly. We found that physiological
hyperinsulinemia in awake, behaving mice does not increase CNS insulin to an
appreciable level yet modestly increases extracellular A?. We also found that the
brain of aged APP/PS1 mice was not insulin resistant, contrary to the current
state of the literature. These results further elucidate the relationship between
insulin, the brain, and AD and its conflicting roles as both a risk factor and
potential treatment.
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