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Amyloid-β Protein Modulates Insulin Signaling in Presynaptic Terminals

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Abstract

Synaptic loss is a major neuropathological correlate of memory decline as a result of Alzheimer’s disease (AD). This phenomenon appears to be aggravated by soluble amyloid-β (Aβ) oligomers causing presynaptic terminals to be particularly vulnerable to damage. Furthermore, insulin is known to participate in synaptic plasticity through the activation of the insulin receptor (IR) and the PI3K signaling pathway, while low concentrations of soluble Aβ and Aβ oligomers aberrantly modulate IR function in cultured neurons. To further examine how Aβ and insulin interact in the pathology of AD, the present work analyzes the effect of insulin and Aβ in the activation of the IR/PI3K pathway in synaptosomes. We found that insulin increased mitochondrial activity and IR/Akt phosphorylation in synaptosomes taken from both hippocampus and cortex. Also, pretreatment with Aβ antagonized insulin’s effect on hippocampal synaptosomes, but not vice versa. These results show that Aβ can reduce responsiveness to insulin. Combined with evidence that insulin desensitization can increase the risk of developing AD, our results suggest that the initial mechanism that impairs synaptic maintenance in AD might start with Aβ changes in insulin sensitivity.

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Acknowledgments

This work was supported by grants from CONACYT and PAPIIT, UNAM. David Heras-Sandoval is supported by CONACYT 217779 and is currently in the PhD program: Doctorado en Ciencias Biomédicas, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México.

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  1. Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico D.F., Mexico

    David Heras-Sandoval, Patricia Ferrera & Clorinda Arias

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  1. David Heras-Sandoval
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  2. Patricia Ferrera
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  3. Clorinda Arias
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Correspondence to Clorinda Arias.

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Heras-Sandoval, D., Ferrera, P. & Arias, C. Amyloid-β Protein Modulates Insulin Signaling in Presynaptic Terminals. Neurochem Res 37, 1879–1885 (2012). https://doi.org/10.1007/s11064-012-0800-7

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  • DOI: https://doi.org/10.1007/s11064-012-0800-7

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