DIET INFLUENCES PERIPHERAL AMYLOID BETA METABOLISM: A ROLE FOR CIRCULATING INSULIN-LIKE GROWTH FACTOR I

Obesity is a risk factor for Alzheimers 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 on brain A{beta} load, a major landmark of AD pathology. Overweight mice showed increased peripheral A{beta} clearance by the liver, the major site of elimination of systemic A{beta}, but unaltered brain A{beta} levels. Since circulating insulin-like growth factor I (IGF-I) modulates brain A{beta} clearance, and is increased in serum of overweight mice, we determined whether it affects peripheral A{beta} clearance. We found that A{beta} uptake by hepatocytes is stimulated by IGF-I. Moreover, mice with low serum IGF-I levels show reduced peripheral A{beta} clearance. In the brain, IGF-I favored association of its receptor (IGF-IR) with A{beta} precursor protein (APP), and at the same time stimulated non-amyloidogenic processing of APP in astrocytes, as indicated by an increased sAPP/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 less activation of brain IGF-IR phosphorylation and APP/IGF-IR association was found in overweight mice as compared to lean controls. Collectively, these results indicate that 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} clearance probably because its brain entrance is reduced.