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’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 insu...
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doaj-4b53957ae76a44a5ab8b6421cd560da32020-12-19T00:03:08ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-12-01219675967510.3390/ijms21249675Circulating Insulin-Like Growth Factor I Is Involved in the Effect of High Fat Diet on Peripheral Amyloid β ClearanceRaquel Herrero-Labrador0Angel Trueba-Saiz1Laura Martinez-Rachadell2Ma Estrella Fernandez de Sevilla3Jonathan A. Zegarra-Valdivia4Jaime Pignatelli5Sonia Diaz-Pacheco6Ana M. Fernandez7Ignacio Torres Aleman8Cajal Institute, CSIC, 28002 Madrid, SpainCajal Institute, CSIC, 28002 Madrid, SpainCajal Institute, CSIC, 28002 Madrid, SpainCajal Institute, CSIC, 28002 Madrid, SpainCajal Institute, CSIC, 28002 Madrid, SpainCajal Institute, CSIC, 28002 Madrid, SpainCajal Institute, CSIC, 28002 Madrid, SpainCajal Institute, CSIC, 28002 Madrid, SpainCajal Institute, CSIC, 28002 Madrid, SpainObesity 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.https://www.mdpi.com/1422-0067/21/24/9675dietAβ clearanceIGF-IAlzheimer disease |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Raquel Herrero-Labrador Angel Trueba-Saiz Laura Martinez-Rachadell Ma Estrella Fernandez de Sevilla Jonathan A. Zegarra-Valdivia Jaime Pignatelli Sonia Diaz-Pacheco Ana M. Fernandez Ignacio Torres Aleman |
spellingShingle |
Raquel Herrero-Labrador Angel Trueba-Saiz Laura Martinez-Rachadell Ma Estrella Fernandez de Sevilla Jonathan A. Zegarra-Valdivia Jaime Pignatelli Sonia Diaz-Pacheco Ana M. Fernandez Ignacio Torres Aleman Circulating Insulin-Like Growth Factor I Is Involved in the Effect of High Fat Diet on Peripheral Amyloid β Clearance International Journal of Molecular Sciences diet Aβ clearance IGF-I Alzheimer disease |
author_facet |
Raquel Herrero-Labrador Angel Trueba-Saiz Laura Martinez-Rachadell Ma Estrella Fernandez de Sevilla Jonathan A. Zegarra-Valdivia Jaime Pignatelli Sonia Diaz-Pacheco Ana M. Fernandez Ignacio Torres Aleman |
author_sort |
Raquel Herrero-Labrador |
title |
Circulating Insulin-Like Growth Factor I Is Involved in the Effect of High Fat Diet on Peripheral Amyloid β Clearance |
title_short |
Circulating Insulin-Like Growth Factor I Is Involved in the Effect of High Fat Diet on Peripheral Amyloid β Clearance |
title_full |
Circulating Insulin-Like Growth Factor I Is Involved in the Effect of High Fat Diet on Peripheral Amyloid β Clearance |
title_fullStr |
Circulating Insulin-Like Growth Factor I Is Involved in the Effect of High Fat Diet on Peripheral Amyloid β Clearance |
title_full_unstemmed |
Circulating Insulin-Like Growth Factor I Is Involved in the Effect of High Fat Diet on Peripheral Amyloid β Clearance |
title_sort |
circulating insulin-like growth factor i is involved in the effect of high fat diet on peripheral amyloid β clearance |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2020-12-01 |
description |
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. |
topic |
diet Aβ clearance IGF-I Alzheimer disease |
url |
https://www.mdpi.com/1422-0067/21/24/9675 |
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