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Monomeric ß-amyloid interacts with type-1 insulin-like growth factor receptors to provide energy supply to neurons.

Giuffrida ML, Tomasello MF, Pandini G, Caraci F, Battaglia G, Busceti C, Di Pietro P, Pappalardo G, Attanasio F, Chiechio S, Bagnoli S, Nacmias B, Sorbi S, Vigneri R, Rizzarelli E, Nicoletti F, Copani A - Front Cell Neurosci (2015)

Bottom Line: APP- neurons failed to enhance depolarization-stimulated glucose uptake unless exogenous monomeric Aß1-42 was added.These data suggest that Aß1-42 monomers were critical for maintaining neuronal glucose homeostasis.Accordingly, exogenous Aß1-42 monomers were able to rescue the low levels of glucose consumption observed in brain slices from AD mutant mice.

View Article: PubMed Central - PubMed

Affiliation: National Research Council, Institute of Biostructure and Bioimaging Catania, Italy.

ABSTRACT
ß-amyloid (Aß1-42) is produced by proteolytic cleavage of the transmembrane type-1 protein, amyloid precursor protein. Under pathological conditions, Aß1-42self-aggregates into oligomers, which cause synaptic dysfunction and neuronal loss, and are considered the culprit of Alzheimer's disease (AD). However, Aß1-42 is mainly monomeric at physiological concentrations, and the precise role of monomeric Aß1-42 in neuronal function is largely unknown. We report that the monomer of Aß1-42 activates type-1 insulin-like growth factor receptors and enhances glucose uptake in neurons and peripheral cells by promoting the translocation of the Glut3 glucose transporter from the cytosol to the plasma membrane. In neurons, activity-dependent glucose uptake was blunted after blocking endogenous Aß production, and re-established in the presence of cerebrospinal fluid Aß. APP- neurons failed to enhance depolarization-stimulated glucose uptake unless exogenous monomeric Aß1-42 was added. These data suggest that Aß1-42 monomers were critical for maintaining neuronal glucose homeostasis. Accordingly, exogenous Aß1-42 monomers were able to rescue the low levels of glucose consumption observed in brain slices from AD mutant mice.

No MeSH data available.


Related in: MedlinePlus

Peripheral effects of Aß1−42 monomers. (A) Aß1−42 monomers transiently increased blood glucose levels in CD1 male mice undergoing a glucose tolerance test (GTT). This effect was mimicked by the Ac-KLVFF-NH2 peptide and by IGF-1. Fasted mice were i.p. injected with either Aß1−42 monomers (mAß), KLVFF monomers or IGF-1 5 min before glucose loading (2 g/kg). Plots represent the fold increase of glucose levels over basal in 4 animals per experimental condition. *Significantly different from control (CTRL) at p < 0.05 (One-Way Anova + Fisher's LSD test). Data are from one experiment repeated three times with similar results. (B) Ac-KLVFF-NH2 monomers sustained the rise in blood glucose levels in APP- mice undergoing GTT. Mice, either C57BL/6J (WT) or APP-, were i.p. injected with the Ac-KLVFF-NH2 peptide 15 min after glucose load. *Significantly different from APP--saline at p < 0.001 (n = 4–10 animals/group, One-Way Anova + Fisher's LSD test). (C) Aß1−42 monomers reduced glucose-stimulated insulin release in pancreatic INS-1E cells. This effect was mimicked by the Ac-KLVFF-NH2 peptide and was prevented by the IGF-IR antagonist, PPP. Data, representative of three experiments, are fold change of glucose-stimulated insulin release. Significantly different from the 15 mM glucose condition (*), or the respective controls (#) at p < 0.05 and (One-Way Anova + Fisher's LSD test).
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Figure 6: Peripheral effects of Aß1−42 monomers. (A) Aß1−42 monomers transiently increased blood glucose levels in CD1 male mice undergoing a glucose tolerance test (GTT). This effect was mimicked by the Ac-KLVFF-NH2 peptide and by IGF-1. Fasted mice were i.p. injected with either Aß1−42 monomers (mAß), KLVFF monomers or IGF-1 5 min before glucose loading (2 g/kg). Plots represent the fold increase of glucose levels over basal in 4 animals per experimental condition. *Significantly different from control (CTRL) at p < 0.05 (One-Way Anova + Fisher's LSD test). Data are from one experiment repeated three times with similar results. (B) Ac-KLVFF-NH2 monomers sustained the rise in blood glucose levels in APP- mice undergoing GTT. Mice, either C57BL/6J (WT) or APP-, were i.p. injected with the Ac-KLVFF-NH2 peptide 15 min after glucose load. *Significantly different from APP--saline at p < 0.001 (n = 4–10 animals/group, One-Way Anova + Fisher's LSD test). (C) Aß1−42 monomers reduced glucose-stimulated insulin release in pancreatic INS-1E cells. This effect was mimicked by the Ac-KLVFF-NH2 peptide and was prevented by the IGF-IR antagonist, PPP. Data, representative of three experiments, are fold change of glucose-stimulated insulin release. Significantly different from the 15 mM glucose condition (*), or the respective controls (#) at p < 0.05 and (One-Way Anova + Fisher's LSD test).

Mentions: Physiological concentrations of IGF-1 inhibit insulin secretion from pancreatic ß cells (Van Schravendijk et al., 1990). Similarly to IGF-1, monomers of Aß1−42 and Ac-KLVFF-NH2 (injected i.p. to obtain plasma concentrations of 100 nM) caused a transient increase in blood glucose levels in CD1 mice undergoing a glucose tolerance test (GTT), which reflects the inhibition of insulin secretion (Figure 6A). Blood glucose levels during GTT were higher in the C57BL/6J strain than in the CD1 strain, consistent with the evidence that C57BL/6J mice have an inherited impaired glucose tolerance (Toye et al., 2005). In C57BL/6J mice, monomers of Ac-KLVFF-NH2 did not affect significantly blood glucose levels during GTT; however, in the congenic APP- mice undergoing GTT, monomers of Ac-KLVFF-NH2 were able to sustain the rise in blood glucose levels when injected 15 min after glucose load (Figure 6B).


Monomeric ß-amyloid interacts with type-1 insulin-like growth factor receptors to provide energy supply to neurons.

Giuffrida ML, Tomasello MF, Pandini G, Caraci F, Battaglia G, Busceti C, Di Pietro P, Pappalardo G, Attanasio F, Chiechio S, Bagnoli S, Nacmias B, Sorbi S, Vigneri R, Rizzarelli E, Nicoletti F, Copani A - Front Cell Neurosci (2015)

Peripheral effects of Aß1−42 monomers. (A) Aß1−42 monomers transiently increased blood glucose levels in CD1 male mice undergoing a glucose tolerance test (GTT). This effect was mimicked by the Ac-KLVFF-NH2 peptide and by IGF-1. Fasted mice were i.p. injected with either Aß1−42 monomers (mAß), KLVFF monomers or IGF-1 5 min before glucose loading (2 g/kg). Plots represent the fold increase of glucose levels over basal in 4 animals per experimental condition. *Significantly different from control (CTRL) at p < 0.05 (One-Way Anova + Fisher's LSD test). Data are from one experiment repeated three times with similar results. (B) Ac-KLVFF-NH2 monomers sustained the rise in blood glucose levels in APP- mice undergoing GTT. Mice, either C57BL/6J (WT) or APP-, were i.p. injected with the Ac-KLVFF-NH2 peptide 15 min after glucose load. *Significantly different from APP--saline at p < 0.001 (n = 4–10 animals/group, One-Way Anova + Fisher's LSD test). (C) Aß1−42 monomers reduced glucose-stimulated insulin release in pancreatic INS-1E cells. This effect was mimicked by the Ac-KLVFF-NH2 peptide and was prevented by the IGF-IR antagonist, PPP. Data, representative of three experiments, are fold change of glucose-stimulated insulin release. Significantly different from the 15 mM glucose condition (*), or the respective controls (#) at p < 0.05 and (One-Way Anova + Fisher's LSD test).
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Related In: Results  -  Collection

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Figure 6: Peripheral effects of Aß1−42 monomers. (A) Aß1−42 monomers transiently increased blood glucose levels in CD1 male mice undergoing a glucose tolerance test (GTT). This effect was mimicked by the Ac-KLVFF-NH2 peptide and by IGF-1. Fasted mice were i.p. injected with either Aß1−42 monomers (mAß), KLVFF monomers or IGF-1 5 min before glucose loading (2 g/kg). Plots represent the fold increase of glucose levels over basal in 4 animals per experimental condition. *Significantly different from control (CTRL) at p < 0.05 (One-Way Anova + Fisher's LSD test). Data are from one experiment repeated three times with similar results. (B) Ac-KLVFF-NH2 monomers sustained the rise in blood glucose levels in APP- mice undergoing GTT. Mice, either C57BL/6J (WT) or APP-, were i.p. injected with the Ac-KLVFF-NH2 peptide 15 min after glucose load. *Significantly different from APP--saline at p < 0.001 (n = 4–10 animals/group, One-Way Anova + Fisher's LSD test). (C) Aß1−42 monomers reduced glucose-stimulated insulin release in pancreatic INS-1E cells. This effect was mimicked by the Ac-KLVFF-NH2 peptide and was prevented by the IGF-IR antagonist, PPP. Data, representative of three experiments, are fold change of glucose-stimulated insulin release. Significantly different from the 15 mM glucose condition (*), or the respective controls (#) at p < 0.05 and (One-Way Anova + Fisher's LSD test).
Mentions: Physiological concentrations of IGF-1 inhibit insulin secretion from pancreatic ß cells (Van Schravendijk et al., 1990). Similarly to IGF-1, monomers of Aß1−42 and Ac-KLVFF-NH2 (injected i.p. to obtain plasma concentrations of 100 nM) caused a transient increase in blood glucose levels in CD1 mice undergoing a glucose tolerance test (GTT), which reflects the inhibition of insulin secretion (Figure 6A). Blood glucose levels during GTT were higher in the C57BL/6J strain than in the CD1 strain, consistent with the evidence that C57BL/6J mice have an inherited impaired glucose tolerance (Toye et al., 2005). In C57BL/6J mice, monomers of Ac-KLVFF-NH2 did not affect significantly blood glucose levels during GTT; however, in the congenic APP- mice undergoing GTT, monomers of Ac-KLVFF-NH2 were able to sustain the rise in blood glucose levels when injected 15 min after glucose load (Figure 6B).

Bottom Line: APP- neurons failed to enhance depolarization-stimulated glucose uptake unless exogenous monomeric Aß1-42 was added.These data suggest that Aß1-42 monomers were critical for maintaining neuronal glucose homeostasis.Accordingly, exogenous Aß1-42 monomers were able to rescue the low levels of glucose consumption observed in brain slices from AD mutant mice.

View Article: PubMed Central - PubMed

Affiliation: National Research Council, Institute of Biostructure and Bioimaging Catania, Italy.

ABSTRACT
ß-amyloid (Aß1-42) is produced by proteolytic cleavage of the transmembrane type-1 protein, amyloid precursor protein. Under pathological conditions, Aß1-42self-aggregates into oligomers, which cause synaptic dysfunction and neuronal loss, and are considered the culprit of Alzheimer's disease (AD). However, Aß1-42 is mainly monomeric at physiological concentrations, and the precise role of monomeric Aß1-42 in neuronal function is largely unknown. We report that the monomer of Aß1-42 activates type-1 insulin-like growth factor receptors and enhances glucose uptake in neurons and peripheral cells by promoting the translocation of the Glut3 glucose transporter from the cytosol to the plasma membrane. In neurons, activity-dependent glucose uptake was blunted after blocking endogenous Aß production, and re-established in the presence of cerebrospinal fluid Aß. APP- neurons failed to enhance depolarization-stimulated glucose uptake unless exogenous monomeric Aß1-42 was added. These data suggest that Aß1-42 monomers were critical for maintaining neuronal glucose homeostasis. Accordingly, exogenous Aß1-42 monomers were able to rescue the low levels of glucose consumption observed in brain slices from AD mutant mice.

No MeSH data available.


Related in: MedlinePlus