No abstract

Aberrant protein aggregation is a common feature of late-onset neurodegenerative diseases, including Alzheimer's disease, which is associated with the misassembly of the Abeta(1-42) peptide. Aggregation-mediated Abeta(1-42) toxicity was reduced in Caenorhabditis elegans when aging was slowed by decreased insulin/insulin growth factor-1-like signaling (IIS). The downstream transcription factors, heat shock factor 1, and DAF-16 regulate opposing disaggregation and aggregation activities to promote cellular survival in response to constitutive toxic protein aggregation. Because the IIS pathway is central to the regulation of longevity and youthfulness in worms, flies, and mammals, these results suggest a mechanistic link between the aging process and aggregation-mediated proteotoxicity.

Summary The Insulin/IGF signaling pathway (IIS) is a prominent 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 the Alzheimer's-like disease symptoms including reduced behavioral impairment, neruoinflammation, neuronal and synpatic loss. This protection is correlated with the hyper-aggregation of Aβ leading to tightly packed, ordered plaques suggesting that one aspect of the protection conferred by reduced IGF signaling is the possible 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.