Obesity is a risk factor for Alzheimer disease (AD), but underlying mechanisms are not clear. We analyzed peripheral clearance of amyloid-beta (Abeta) in overweight mice because its systemic elimination may impact on brain Abeta load, a major landmark of AD pathology. Overweight mice showed increased peripheral Abeta clearance by the liver, the major site of elimination of systemic Abeta, but unaltered brain Abeta levels. Since circulating insulin-like growth factor I (IGF-I) modulates brain Abeta clearance, and is increased in serum of overweight mice, we determined whether it affects peripheral Abeta clearance. We found that Abeta uptake by hepatocytes is stimulated by IGF-I. Moreover, mice with low serum IGF-I levels show reduced peripheral Abeta clearance. In the brain, IGF-I favored association of its receptor (IGF-IR) with Abeta precursor protein (APP) and at the same time stimulated non-amyloidogenic processing of APP in astrocytes, as indicated by an increased sAPPalpha/sAPPbeta 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 Abeta without affecting brain Abeta load. Increased serum IGF-I likely contributes to enhanced peripheral Abeta clearance in overweight mice, without affecting brain Abeta clearance probably because its brain entrance is reduced.Competing Interest StatementThe authors have declared no competing interest.
bioRxiv Subject Collection: Neuroscience