title: Reduced IGF-1 signaling delays age-associated proteotoxicity in mice.
abstract: 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, Abeta. 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 Abeta leading to tightly packed, ordered plaques, suggesting that one aspect of the protection conferred by reduced IGF signaling is the sequestration of soluble Abeta oligomers into dense aggregates of lower toxicity. These findings indicate that the IGF signaling-regulated mechanism that protects from Abeta 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.
authors.affiliation: Howard Hughes Medical Institute, Glenn Center for Aging Research, Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Ehud
authors.initials: E
authors.lastname: Cohen
authors.forename: Johan F
authors.initials: JF
authors.lastname: Paulsson
authors.forename: Pablo
authors.initials: P
authors.lastname: Blinder
authors.forename: Tal
authors.initials: T
authors.lastname: Burstyn-Cohen
authors.forename: Deguo
authors.initials: D
authors.lastname: Du
authors.forename: Gabriela
authors.initials: G
authors.lastname: Estepa
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.forename: Hang M
authors.initials: HM
authors.lastname: Pham
authors.forename: Martin
authors.initials: M
authors.lastname: Holzenberger
authors.forename: Jeffery W
authors.initials: JW
authors.lastname: Kelly
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Andrew
authors.initials: A
authors.lastname: Dillin
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008136:Longevity; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016229:Amyloid beta-Peptides; C508853:PSEN1 protein, human; D053764:Presenilin-1; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1