Reduced IGF-1 signaling delays age-associated proteotoxicity in mice.
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.
Cohen
Ehud
E
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.
Paulsson
Johan F
JF
Blinder
Pablo
P
Burstyn-Cohen
Tal
T
Du
Deguo
D
Estepa
Gabriela
G
Adame
Anthony
A
Pham
Hang M
HM
Holzenberger
Martin
M
Kelly
Jeffery W
JW
Masliah
Eliezer
E
Dillin
Andrew
A
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
D016229:Amyloid beta-Peptides; C508853:PSEN1 protein, human; D053764:Presenilin-1; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1