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PMID: 20005808 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Reduced IGF-1 signaling delays age-associated proteotoxicity in mice.

Cell ·Vol. 139 ·No. 6 ·2009-12-11 ·Pages 1157-69

Cohen E, Paulsson JF, Blinder P, Burstyn-Cohen T, Du D, Estepa G, Adame A, Pham HM, Holzenberger M, Kelly JW, Masliah E, Dillin A

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.

MeSH Terms
Alzheimer Disease/metabolism,physiopathology Amyloid beta-Peptides/metabolism Animals Humans Insulin-Like Growth Factor I/metabolism Longevity Male Mice Mice, Transgenic Presenilin-1/genetics,metabolism Receptor, IGF Type 1/metabolism Signal Transduction
Chemicals
Amyloid beta-Peptides PSEN1 protein, human Presenilin-1 Insulin-Like Growth Factor I Receptor, IGF Type 1
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Cohen Ehud
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
Blinder Pablo
Burstyn-Cohen Tal
Du Deguo
Estepa Gabriela
Adame Anthony
Pham Hang M
Holzenberger Martin
Kelly Jeffery W
Masliah Eliezer
Dillin Andrew
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2009.11.014
Published
2009-12-11
Pages
1157-69
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC3017511
Subset
IM
Grants
NIA NIH HHS · P01 AG031097 · United States
NIA NIH HHS · P01 AG031097-01A18147 · United States
External Links
PubMed source DOI: 10.1016/j.cell.2009.11.014 PMC Full Text View journal details
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