Neuroprotective astrocyte-derived insulin/insulin-like growth factor 1 stimulates endocytic processing and extracellular release of neuron-bound Aβ oligomers

Jason Pitt, Kyle C. Wilcox, Vanessa Tortelli, Luan Pereira Diniz, Maira S. Oliveira, Cassandra Dobbins, Xiao Wen Yu, Sathwik Nandamuri, Flávia C.A. Gomes, Nadia DiNunno, Kirsten L. Viola, Fernanda G. De Felice, Sergio T. Ferreira, William L. Klein*

*Corresponding author for this work

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Synaptopathy underlying memory deficits in Alzheimer's disease (AD) is increasingly thought to be instigated by toxic oligomers of the amyloid beta peptide (AβOs). Given the long latency and incomplete penetrance of AD dementia with respect to Aβ pathology, we hypothesized that factors present in the CNS may physiologically protect neurons from the deleterious impact of AβOs. Here we employed physically separated neuron-astrocyte cocultures to investigate potential non-cell autonomous neuroprotective factors influencing AβO toxicity. Neurons cultivated in the absence of an astrocyte feeder layer showed abundant AβO binding to dendritic processes and associated synapse deterioration. In contrast, neurons in the presence of astrocytes showed markedly reduced AβO binding and synaptopathy. Results identified the protective factors released by astrocytes as insulin and insulin-like growth factor-1 (IGF1). The protective mechanism involved release of newly bound AβOs into the extracellular medium dependent upon trafficking that was sensitive to exosome pathway inhibitors. Delaying insulin treatment led to AβO binding that was no longer releasable. The neuroprotective potential of astrocytes was itself sensitive to chronic AβO exposure, which reduced insulin/IGF1 expression. Our findings support the idea that physiological protection against synaptotoxic AβOs can be mediated by astrocyte-derived insulin/IGF1, but that this protection itself is vulnerable to AβO buildup.

Original languageEnglish (US)
Pages (from-to)2623-2636
Number of pages14
JournalMolecular biology of the cell
Volume28
Issue number20
DOIs
StatePublished - Oct 1 2017

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Pitt, J., Wilcox, K. C., Tortelli, V., Diniz, L. P., Oliveira, M. S., Dobbins, C., Yu, X. W., Nandamuri, S., Gomes, F. C. A., DiNunno, N., Viola, K. L., De Felice, F. G., Ferreira, S. T., & Klein, W. L. (2017). Neuroprotective astrocyte-derived insulin/insulin-like growth factor 1 stimulates endocytic processing and extracellular release of neuron-bound Aβ oligomers. Molecular biology of the cell, 28(20), 2623-2636. https://doi.org/10.1091/mbc.E17-06-0416