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

Raquel Herrero-Labrador,Laura Martinez-Rachadell,Jaime Pignatelli,Angel Trueba-Saiz,Ignacio Torres Aleman,Jonathan A Zegarra-Valdivia,Sonia Diaz-Pacheco,Ana M Fernandez,Mᵃ Estrella Fernandez De Sevilla

doi:10.3390/ijms21249675

Abstract

Obesity is a risk factor for Alzheimer’s disease (AD), but underlying mechanisms are not clear. We analyzed peripheral clearance of amyloid β (Aβ) in overweight mice because its systemic elimination may impact brain Aβ 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 Aβ clearance and is increased in the serum of overweight mice. Overweight mice showed increased Aβ accumulation by the liver, the major site of elimination of systemic Aβ, but unaltered brain Aβ levels. We also found that Aβ accumulation by hepatocytes is stimulated by IGF-I, and that mice with low serum IGF-I levels show reduced liver Aβ accumulation—ameliorated by IGF-I administration, and unchanged brain Aβ levels. In the brain, IGF-I favored the association of its receptor (IGF-IR) with the Aβ precursor protein (APP), and at the same time, stimulated non-amyloidogenic processing of APP in astrocytes, as indicated by an increased sAPPα/sAPPβ 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 Aβ without affecting brain Aβ load. Increased serum IGF-I likely contributes to enhanced peripheral Aβ clearance in overweight mice, without affecting brain Aβ load probably because its brain entrance is reduced.

Highlights

Obesity is considered a risk factor for Alzheimer’s disease (AD) [1,2,3]
Since serum insulin-like growth factor I (IGF-I) levels are increased in overweight mice (Figure 1B), we determined whether brain IGF-I is correspondingly higher, as serum IGF-I crosses the BBB [24]
We found that IGF-I promoted Amyloid β (Aβ) uptake by astrocytes (Figure 4A) while it decreased it in microglia (Figure 4B)

Summary

Introduction

Obesity is considered a risk factor for AD [1,2,3]. Taking into account the worrying worldwide prevalence of obesity and dementia [8,9], greater knowledge of possible links between the two conditions is imperative. Amyloid β (Aβ) handling may be one such link, as this peptide is considered a major pathogenic factor in AD and obesity-associated inflammation [10] may interfere with its elimination from the brain. We recently proposed that insulin peptides such as insulin and insulin-like growth factor I (IGF-I), may be involved in the connection between lifestyle and AD risk [11], apparently, contradictory evidence links IGF-I with AD. Hepatocytes, the main source of circulating IGF-I [14], are the major disposal system for circulating Aβ in mice [15], and previous evidence has shown that insulin, a hormone closely related to IGF-I, favors Aβ uptake by hepatocytes [16]

Methods

Results

Conclusion