A network of insulin peptides regulate glucose uptake by astrocytes: Potential new druggable targets for brain hypometabolism

Fernández, Adolfo; Hernandez, Edwin; Guerrero-Gómez, David; Miranda‐Vizuete, Antonio; Torres‐Alemán, Ignacio

doi:10.1016/j.neuropharm.2017.08.034

Cited by 21 publications

(14 citation statements)

References 69 publications

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“…Interestingly, insulin also enhances the degradation of Aβ and its clearance in astrocytes [66], and hepatocytes [26], respectively. Thus, these two closely related hormones may modulate Aβ disposal in a concerted manner, as previously reported for glucose handling [67].…”

Section: Discussionsupporting

confidence: 70%

Circulating insulin-like growth factor I is involved in the effect of diet on peripheral amyloid β clearance

Herrero-Labrador

Trueba-Saiz

Martinez-Rachadell

et al. 2020

Preprint

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BackgroundObesity is a risk factor for Alzheimer´s disease (AD), but underlying mechanisms are not clear.MethodsWe analyzed peripheral clearance of amyloid β (Aβ) in overweight mice because its systemic elimination may impact on 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 serum of overweight mice. Results Overweight mice showed increased peripheral Aβ clearance by the liver, the major site of elimination of systemic Aβ, but unaltered brain Aβ levels. We also found that Aβ clearance by hepatocytes is stimulated by IGF-I, and that mice with low serum IGF-I levels show reduced peripheral Aβ clearance and unchanged brain Aβ levels. In the brain, IGF-I favored association of its receptor (IGF-IR) with 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 was found in overweight mice as compared to lean controls. Conclusions Collectively, these results indicate that 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 clearance probably because its brain entrance is reduced.

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Section: Discussionsupporting

confidence: 70%

Circulating insulin-like growth factor I is involved in the effect of diet on peripheral amyloid β clearance

Herrero-Labrador

Trueba-Saiz

Martinez-Rachadell

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Interestingly, insulin also enhances the degradation of Aβ and its clearance in astrocytes (54), and hepatocytes (26), respectively. Thus, these two closely related hormones may modulate Aβ disposal in a concerted manner, as previously reported for glucose handling (55).…”

Section: Discussionsupporting

confidence: 70%

Diet Influences Peripheral Amyloid Β Metabolism: A Role for Circulating Insulin-Like Growth Factor I

Raquel

Trueba-Saiz

Martinez-Rachadell

et al. 2020

Preprint

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AbstractObesity 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 on brain Aβ load, a major landmark of AD pathology. Overweight mice showed increased peripheral Aβ clearance by the liver, the major site of elimination of systemic Aβ, but unaltered brain Aβ levels. Since circulating insulin-like growth factor I (IGF-I) modulates brain Aβ clearance, and is increased in serum of overweight mice, we determined whether it affects peripheral Aβ clearance. We found that Aβ uptake by hepatocytes is stimulated by IGF-I. Moreover, mice with low serum IGF-I levels show reduced peripheral Aβ clearance. In the brain, IGF-I favored association of its receptor (IGF-IR) with 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 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 Aβ without affecting brain Aβ load. Increased serum IGF-I likely contributes to enhanced peripheral Aβ clearance in overweight mice, without affecting brain Aβ clearance probably because its brain entrance is reduced.

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“…Astrocytes play an integral role in the maintenance and modulation of neuronal health and function by supplying important trophic factors, such as IGF-1, and energy substrates necessary for neuronal function [22] , [23] , [24] . IGF-1 signaling regulates key aspects of astrocyte function, including glucose uptake [25] , [26] , [27] , regulation of glutamate transport [28] , and protection from oxidative stress [29] in the brain. Reduced serum IGF-1 and its signaling in astrocytes is also associated with Alzheimer's disease progression and pathology [30] , [31] .…”

Section: Introductionmentioning

confidence: 99%

Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-β uptake in astrocytes

Logan

Pharaoh

Marlin

et al. 2018

Molecular Metabolism

123

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ObjectiveA decline in mitochondrial function and biogenesis as well as increased reactive oxygen species (ROS) are important determinants of aging. With advancing age, there is a concomitant reduction in circulating levels of insulin-like growth factor-1 (IGF-1) that is closely associated with neuronal aging and neurodegeneration. In this study, we investigated the effect of the decline in IGF-1 signaling with age on astrocyte mitochondrial metabolism and astrocyte function and its association with learning and memory.MethodsLearning and memory was assessed using the radial arm water maze in young and old mice as well as tamoxifen-inducible astrocyte-specific knockout of IGFR (GFAP-CreTAM/igfrf/f). The impact of IGF-1 signaling on mitochondrial function was evaluated using primary astrocyte cultures from igfrf/f mice using AAV-Cre mediated knockdown using Oroboros respirometry and Seahorse assays.ResultsOur results indicate that a reduction in IGF-1 receptor (IGFR) expression with age is associated with decline in hippocampal-dependent learning and increased gliosis. Astrocyte-specific knockout of IGFR also induced impairments in working memory. Using primary astrocyte cultures, we show that reducing IGF-1 signaling via a 30–50% reduction IGFR expression, comparable to the physiological changes in IGF-1 that occur with age, significantly impaired ATP synthesis. IGFR deficient astrocytes also displayed altered mitochondrial structure and function and increased mitochondrial ROS production associated with the induction of an antioxidant response. However, IGFR deficient astrocytes were more sensitive to H2O2-induced cytotoxicity. Moreover, IGFR deficient astrocytes also showed significantly impaired glucose and Aβ uptake, both critical functions of astrocytes in the brain.ConclusionsRegulation of astrocytic mitochondrial function and redox status by IGF-1 is essential to maintain astrocytic function and coordinate hippocampal-dependent spatial learning. Age-related astrocytic dysfunction caused by diminished IGF-1 signaling may contribute to the pathogenesis of Alzheimer's disease and other age-associated cognitive pathologies.

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A network of insulin peptides regulate glucose uptake by astrocytes: Potential new druggable targets for brain hypometabolism

Cited by 21 publications

References 69 publications

Circulating insulin-like growth factor I is involved in the effect of diet on peripheral amyloid β clearance

Circulating insulin-like growth factor I is involved in the effect of diet on peripheral amyloid β clearance

Diet Influences Peripheral Amyloid Β Metabolism: A Role for Circulating Insulin-Like Growth Factor I

Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-β uptake in astrocytes

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