Circulating Insulin-Like Growth Factor I is Involved in the Effect of High Fat Diet on Peripheral Amyloid β Clearance

Obesity is a risk factor for Alzheimer&rsquo
s disease (AD), but underlying mechanisms are not clear. We analyzed peripheral clearance of amyloid &beta
(A&beta
) in overweight mice because its systemic elimination may impact brain A&beta
load, a major landmark of AD pathology. We also analyzed whether circulating insulin-like growth factor I (IGF-I) intervenes in the effects of overweight as this growth factor modulates brain A&beta
clearance and is increased in the serum of overweight mice. Overweight mice showed increased A&beta
accumulation by the liver, the major site of elimination of systemic A&beta
but unaltered brain A&beta
levels. We also found that A&beta
accumulation by hepatocytes is stimulated by IGF-I, and that mice with low serum IGF-I levels show reduced liver A&beta
accumulation&mdash
ameliorated by IGF-I administration, and unchanged brain A&beta
levels. In the brain, IGF-I favored the association of its receptor (IGF-IR) with the A&beta
precursor protein (APP), and at the same time, stimulated non-amyloidogenic processing of APP in astrocytes, as indicated by an increased sAPP&alpha
/sAPP&beta
ratio after IGF-I treatment. Since serum IGF-I enters into the brain in an activity-dependent manner, we analyzed in overweight mice the effect of brain activation by environmental enrichment (EE) on brain IGF-IR phosphorylation and its association to APP, as a readout of IGF-I activity. After EE, significantly reduced brain IGF-IR phosphorylation and APP/IGF-IR association were found in overweight mice as compared to lean controls. Collectively, these results indicate that a high-fat diet influences peripheral clearance of A&beta
without affecting brain A&beta
load. Increased serum IGF-I likely contributes to enhanced peripheral A&beta
clearance in overweight mice, without affecting brain A&beta
load probably because its brain entrance is reduced.