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

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

SUBMITTER: Herrero-Labrador R

PROVIDER: S-EPMC7766006 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Herrero-Labrador Raquel R Trueba-Saiz Angel A Martinez-Rachadell Laura L Fernandez de Sevilla Mᵃ Estrella ME Zegarra-Valdivia Jonathan A JA Pignatelli Jaime J Diaz-Pacheco Sonia S Fernandez Ana M AM Torres Aleman Ignacio I

International journal of molecular sciences 20201218 24

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 inc ...[more]

PMID: 33352990

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

Publications

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

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