The insulin/insulin growth factor (IGF) signaling (IIS) pathway is a key regulator of aging of worms, flies, mice, and likely humans. Delayed aging by IIS reduction protects the nematode C. elegans from toxicity associated with the aggregation of the Alzheimer's disease-linked human peptide, Aβ. We reduced IGF signaling in Alzheimer's model mice and discovered that these animals are protected from Alzheimer's-like disease symptoms, including reduced behavioral impairment, neuroinflammation, and neuronal loss. This protection is correlated with the hyperaggregation of Aβ leading to tightly packed, ordered plaques, suggesting that one aspect of the protection conferred by reduced IGF signaling is the sequestration of soluble Aβ oligomers into dense aggregates of lower toxicity. These findings indicate that the IGF signaling-regulated mechanism that protects from Aβ toxicity is conserved from worms to mammals and point to the modulation of this signaling pathway as a promising strategy for the development of Alzheimer's disease therapy.
Bibliographical noteFunding Information:
We thank Dr. Hyun-Eui Kim for expert assistance with size-exclusion chromatography and Dr. Gustavo Dziewczapolski for assistance with behavioral assay. We thank the McKnight Foundation (A.D.) and NIA P01 AG031097 (A.D., J.W.K., E.M.) for funding. E.C. and A.D. designed and initiated this study. E.C. crossed the mouse strains and performed the behavioral assays, quantitative PCR, ELISA, size exclusion, and WB experiments. T.B.C. performed IHC assays. Immunoelectron microscopy was carried out by J.F.P. D.D. executed in vitro kinetic aggregation assays. P.B. performed image processing of the EM data. A.A. assisted with IHC. G.E. assisted with mice genotyping and behavioral assays. H.M.P. assisted with WB. M.H. provided Igf1r +/− mice and expertise pertinent to Igf1r. E.C., A.D., J.W.K., and E.M. wrote the manuscript. A.D. and J.W.K. are founders of Proteostasis Therepeutics Inc. and disclose no conflict of interest in this study.