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 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.

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

10.21203/rs.3.rs-60930/v1 ◽

2020 ◽

Author(s):

Raquel Herrero-Labrador ◽

Angel Trueba-Saiz ◽

Laura Martinez-Rachadell ◽

Maria Estrella Fernandez de Sevilla ◽

Jonathan A Zegarra-Valdivia ◽

...

Keyword(s):

Growth Factor ◽

Amyloid Β ◽

Dependent Manner ◽

Insulin Like Growth Factor ◽

Factor I ◽

Igf I ◽

Peripheral Clearance ◽

Aβ Clearance ◽

Growth Factor I ◽

The Brain

Abstract 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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DIET INFLUENCES PERIPHERAL AMYLOID β METABOLISM: A ROLE FOR CIRCULATING INSULIN-LIKE GROWTH FACTOR I

10.1101/2020.07.09.180265 ◽

2020 ◽

Author(s):

R. Herrero-Labrador ◽

A. Trueba-Saiz ◽

L. Martinez-Rachadell ◽

E. Fernandez de Sevilla ◽

S. Diaz-Pacheco ◽

...

Keyword(s):

Growth Factor ◽

Amyloid Β ◽

Dependent Manner ◽

Insulin Like Growth Factor ◽

Factor I ◽

Igf I ◽

Peripheral Clearance ◽

Aβ Clearance ◽

Growth Factor I ◽

The Brain

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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Intranasal delivery of erythropoietin plus insulin-like growth factor–I for acute neuroprotection in stroke

Journal of Neurosurgery ◽

10.3171/2009.2.jns081199 ◽

2009 ◽

Vol 111 (1) ◽

pp. 164-170 ◽

Cited By ~ 63

Author(s):

Lauren Fletcher ◽

Sanjivan Kohli ◽

Shane M. Sprague ◽

Robert A. Scranton ◽

Stuart A. Lipton ◽

...

Keyword(s):

Growth Factor ◽

Intranasal Administration ◽

Neuronal Damage ◽

Intraperitoneal Administration ◽

Insulin Like Growth Factor ◽

Efficient Treatment ◽

Factor I ◽

Igf I ◽

Growth Factor I ◽

The Brain

Object Individually, the cytokines erythropoietin (EPO) and insulin-like growth factor–I (IGF-I) have both been shown to reduce neuronal damage significantly in rodent models of cerebral ischemia. The authors have previously shown that EPO and IGF-I, when administered together, provide acute and prolonged neuroprotection in cerebrocortical cultures against N-methyl-d-aspartate–induced apoptosis. The aim of this study was to determine whether intranasally applied EPO plus IGF-I can provide acute neuroprotection in an animal stroke model and to show that intranasal administration is more efficient at delivering EPO plus IGF-I to the brain when compared with intravenous, subcutaneous, or intraperitoneal administration. Methods The EPO and IGF-I were administered intranasally to mice that underwent transient middle cerebral artery occlusion (MCAO). Stroke volumes were measured after 1 hour of MCAO and 24 hours of reperfusion. To evaluate the long-term effects of this treatment, behavioral outcomes were assessed at 3, 30, 60, and 90 days following MCAO. Radiography and liquid scintillation were used to visualize and quantify the uptake of radiolabeled 125I-EPO and 125I–IGF-I into the mouse brain after intranasal, intravenous, subcutaneous, or intraperitoneal administration. Results Intranasal administration of EPO plus IGF-I reduced stroke volumes within 24 hours and improved neurological function in mice up to 90 days after MCAO. The 125I-EPO and 125I–IGF-I were found in the brain within 20 minutes after intranasal administration and accumulated within the injured areas of the brain. In addition, intranasal administration delivered significantly higher levels of the applied 125I-EPO and 125I–IGF-I to the brain compared with intravenous, subcutaneous, or intraperitoneal administration. Conclusions The data demonstrate that intranasal EPO plus IGF-I penetrates into the brain more efficiently than other drug delivery methods and could potentially provide a fast and efficient treatment to prevent chronic effects of stroke.

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Insulin-like Growth Factor I Receptors and IGF-I Actions in Neuronal Cultures from the Brain

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.1993.tb26208.x ◽

1993 ◽

Vol 692 (1 The Role of I) ◽

pp. 89-101 ◽

Cited By ~ 13

Author(s):

BRIAN A. MASTERS ◽

MOHAN K. RAIZADA

Keyword(s):

Growth Factor ◽

Neuronal Cultures ◽

Insulin Like Growth Factor ◽

Factor I ◽

Igf I ◽

Growth Factor I ◽

The Brain

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Effect of brief exercise on circulating insulin-like growth factor I

Journal of Applied Physiology ◽

10.1152/jappl.1994.76.6.2490 ◽

1994 ◽

Vol 76 (6) ◽

pp. 2490-2496 ◽

Cited By ~ 90

Author(s):

J. Cappon ◽

J. A. Brasel ◽

S. Mohan ◽

D. M. Cooper

Keyword(s):

Growth Factor ◽

Lactate Threshold ◽

Exercise Bout ◽

Cycle Ergometer ◽

Insulin Like Growth Factor ◽

High Fat ◽

Factor I ◽

Ergometer Exercise ◽

Igf I ◽

Growth Factor I

An acute insulin-like growth factor I (IGF-I) response to 10 min of above-lactate threshold cycle ergometer exercise was studied in 10 subjects (age 22–35 yr). Each subject exercised on three separate mornings after ingesting one of two isocaloric isovolemic liquid meals high in either fat or glucose or an isovolemic noncaloric placebo. The high-fat meal attenuated the growth hormone (GH) response (Cappon et al., J. Clin. Endocrinol. Metab. 76: 1418–1422, 1993). In contrast, IGF-I increased equally for all protocols [e.g., after the placebo meal IGF-I increased from 21,716 (SE) ng/ml preexercise to 25,316 ng/ml at 10 min of exercise; P < 0.05]. IGF-I peaked by the 10th min of exercise, like GH, and remained significantly elevated for only 20 min of recovery. We tested for possible GH-dependent mechanisms in which circulating IGF-I would increase 12-24 h after exercise. Ten subjects (age 23–32 yr) performed 10 min of above-lactate threshold exercise at 9, 10, and 11 A.M. GH was elevated after the first exercise bout (peak GH 6.05 +/- 1.45 ng/ml; P < 0.001) but was significantly reduced for the second and third bouts (peak GH 2.52 +/- 0.76 and 1.50 +/- 0.40 ng/ml, respectively). No increase in IGF-I was observed by 8 A.M. on the following day. Heavy ergometer exercise led to brief and small increases in circulating IGF-I that were independent of circulating GH.(ABSTRACT TRUNCATED AT 250 WORDS)

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Interdependence of oestrogen and insulin-like growth factor-I in the brain: potential for analysing neuroprotective mechanisms

Journal of Endocrinology ◽

10.1677/joe.1.06058 ◽

2005 ◽

Vol 185 (1) ◽

pp. 11-17 ◽

Cited By ~ 63

Author(s):

Pablo Mendez ◽

Iñigo Azcoitia ◽

Luis Miguel Garcia-Segura

Keyword(s):

Growth Factor ◽

Glycogen Synthase ◽

Reproductive Behaviour ◽

Mitogen Activated Protein Kinase ◽

Neural Function ◽

Insulin Like Growth Factor ◽

Factor I ◽

Igf I ◽

Growth Factor I ◽

The Brain

The actions of oestradiol in the brain involve interaction with growth factors, such as insulin-like growth factor-I (IGF-I). Many cells in the brain co-express receptors for oestradiol and IGF-I and both factors interact to regulate neural function. The relationship of oestrogen receptor α with IGF-I receptor through the mitogen-activated protein kinase and the phosphoinositide 3-kinase signalling pathways may represent the point of convergence used by these two factors to cooperatively modulate neuritic growth, synaptic plasticity, neuroendocrine events, reproductive behaviour and neuronal survival. In addition, Akt and glycogen synthase kinase 3β are key molecular targets to explain the interaction of oestrogen and IGF-I receptor signalling in the promotion of neuroprotection.

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Insulin-Like Growth Factor I Modifies Electrophysiological Properties of Rat Brain Stem Neurons

Journal of Neurophysiology ◽

10.1152/jn.00089.2003 ◽

2003 ◽

Vol 89 (6) ◽

pp. 3008-3017 ◽

Cited By ~ 42

Author(s):

Angel Nuñez ◽

Eva Carro ◽

Ignacio Torres-Aleman

Keyword(s):

Growth Factor ◽

Brain Stem ◽

Dorsal Column ◽

Excitatory Postsynaptic Potential ◽

Insulin Like Growth Factor ◽

Electrophysiological Properties ◽

Factor I ◽

Igf I ◽

Growth Factor I ◽

The Brain

On systemic injection, insulin-like growth factor I (IGF-I) elicits a prolonged increase in the excitability of dorsal column nuclei (DCN) cells in the brain stem as well as other target neurons within the brain. We have explored the cellular mechanisms involved in the stimulatory effects of IGF-I as well as its functional consequences. In a rat slice preparation, IGF-I induced a sustained depolarization of 2–5 mV in 81% of DCN neurons. Depolarization was accompanied with an increase in the input resistance (15%). Voltage-clamp recordings displayed that IGF-I decreased a K+-mediated A current (60%). Furthermore, IGF-I increased, in 78% of cells, the peak amplitude (25%), and rising slope (32%) of the excitatory postsynaptic potential evoked by dorsal column stimulation; in this case, a presynaptic facilitatory process appears to be involved. When anesthetized adult rats are injected in the carotid artery with IGF-I, extracellularly recorded propioceptive DCN neurons not only show increased spike activity but also an expansion of their cutaneous receptive field in 83% of DCN cells. Significantly, the increased excitability evoked by IGF-I in the DCN cells depends both in vivo and in vitro, on activation of p38 mitogen-activated protein kinase (MAPK), a Ser-kinase known to modulate K+ channel activity. We concluded that systemic IGF-I modulated the electrophysiological properties of target neurons within the brain. In turn, these changes probably contribute to functional reorganization processes such as expansion of neuronal receptive fields.

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