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, 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.

[1]  F. Hartl,et al.  Chaperonin TRiC promotes the assembly of polyQ expansion proteins into nontoxic oligomers. , 2006, Molecular cell.

[2]  Stefan Schreiber,et al.  Association of FOXO3A variation with human longevity confirmed in German centenarians , 2009, Proceedings of the National Academy of Sciences.

[3]  Stephen W. Scheff,et al.  Quantitative assessment of cortical synaptic density in Alzheimer's disease , 1990, Neurobiology of Aging.

[4]  D. Borchelt,et al.  Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. , 2004, Human molecular genetics.

[5]  R. Leighty,et al.  Lifelong immunization with human β-amyloid (1–42) protects Alzheimer's transgenic mice against cognitive impairment throughout aging , 2005, Neuroscience.

[6]  D. Leahy,et al.  Functionally significant insulin-like growth factor I receptor mutations in centenarians , 2008, Proceedings of the National Academy of Sciences.

[7]  M. Emond,et al.  Extension of Murine Life Span by Overexpression of Catalase Targeted to Mitochondria , 2005, Science.

[8]  L. Mucke,et al.  Accelerating Amyloid-β Fibrillization Reduces Oligomer Levels and Functional Deficits in Alzheimer Disease Mouse Models* , 2007, Journal of Biological Chemistry.

[9]  Huaxi Xu,et al.  Potential roles of insulin and IGF-1 in Alzheimer's disease , 2003, Trends in Neurosciences.

[10]  Raphael Kopan.  Faculty Opinions recommendation of Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. , 2003 .

[11]  E. Masliah,et al.  Effects of the cholesterol-lowering compound methyl-beta-cyclodextrin in models of alpha-synucleinopathy. , 2006, Journal of neurochemistry.

[12]  D. Selkoe,et al.  Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide , 2007, Nature Reviews Molecular Cell Biology.

[13]  L. Amaducci,et al.  Aging as a major risk for degenerative diseases of the central nervous system: Editorial commentary , 1994, Current opinion in neurology.

[14]  S. Westerheide,et al.  Heat Shock Response Modulators as Therapeutic Tools for Diseases of Protein Conformation* , 2005, Journal of Biological Chemistry.

[15]  Makoto Hashimoto,et al.  Effects of the cholesterol‐lowering compound methyl‐β‐cyclodextrin in models of α‐synucleinopathy , 2006 .

[16]  Clifford J. Woolf,et al.  Pain: Moving from Symptom Control toward Mechanism-Specific Pharmacologic Management , 2004, Annals of Internal Medicine.

[17]  C. Link,et al.  Expression of human beta-amyloid peptide in transgenic Caenorhabditis elegans. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[18]  M. White,et al.  Insulin-like signaling, nutrient homeostasis, and life span. , 2008, Annual review of physiology.

[19]  D. Borchelt,et al.  Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. , 2001, Biomolecular engineering.

[20]  T. Kadowaki,et al.  Neuronal IGF‐1 resistance reduces Aβ accumulation and protects against premature death in a model of Alzheimer's disease , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[21]  Koutarou D. Kimura,et al.  daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. , 1997, Science.

[22]  E. Masliah,et al.  Genetically altered transgenic models of Alzheimer's disease. , 2000, Journal of neural transmission. Supplementum.

[23]  T. Bayer,et al.  Inflammatory changes are tightly associated with neurodegeneration in the brain and spinal cord of the APP/PS1KI mouse model of Alzheimer's disease , 2010, Neurobiology of Aging.

[24]  S. Lindquist,et al.  Hsp104 Catalyzes Formation and Elimination of Self-Replicating Sup35 Prion Conformers , 2004, Science.

[25]  J. Guillou,et al.  Impairment of spatial memory consolidation in APP751SL mice results in cue-guided response , 2008, Neurobiology of Aging.

[26]  Michela Gallagher,et al.  A specific amyloid-beta protein assembly in the brain impairs memory. , 2006, Nature.

[27]  H. Ghosh.  The anti-aging, metabolism potential of SIRT1. , 2008, Current opinion in investigational drugs.

[28]  P. Lansbury,et al.  Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. , 2003, Annual review of neuroscience.

[29]  C. Schnitzler,et al.  BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[30]  M. P. McDonald,et al.  Impaired spatial learning in the APPSwe + PSEN1ΔE9 bigenic mouse model of Alzheimer’s disease , 2007, Genes, brain, and behavior.

[31]  T. Gómez-Isla,et al.  Serum insulin-like growth factor I regulates brain amyloid-beta levels. , 2002, Nature medicine.

[32]  David A. Drachman,et al.  Synaptic loss in Alzheimer's disease and other dementias , 1989, Neurology.

[33]  G. Mancardi,et al.  Fibrous astrocytes in Alzheimer's disease and senile dementia of Alzheimer's type , 2004, Acta Neuropathologica.

[34]  Kimberly Scearce-Levie,et al.  Accelerating amyloid-beta fibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse models. , 2007, The Journal of biological chemistry.

[35]  Martin Holzenberger,et al.  IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice , 2003, Nature.

[36]  P. Muchowski,et al.  Modulation of neurodegeneration by molecular chaperones , 2005, Nature Reviews Neuroscience.

[37]  L. Partridge,et al.  Forkhead transcription factors and ageing , 2008, Oncogene.

[38]  Katsuhiko Yano,et al.  FOXO3A genotype is strongly associated with human longevity , 2008, Proceedings of the National Academy of Sciences.

[39]  Matthias Blüher,et al.  Extended Longevity in Mice Lacking the Insulin Receptor in Adipose Tissue , 2003, Science.

[40]  M. Tatar,et al.  A Mutant Drosophila Insulin Receptor Homolog That Extends Life-Span and Impairs Neuroendocrine Function , 2001, Science.

[41]  Joanna L. Jankowsky,et al.  Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: evidence for augmentation of a 42-specific γ secretase , 2004 .

[42]  S. Heinemann,et al.  Deletion of the α7 Nicotinic Acetylcholine Receptor Gene Improves Cognitive Deficits and Synaptic Pathology in a Mouse Model of Alzheimer's Disease , 2009, The Journal of Neuroscience.

[43]  Richard I. Morimoto,et al.  The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[44]  E. Bézard,et al.  IGF-1 signaling reduces neuro-inflammatory response and sensitivity of neurons to MPTP , 2009, Neurobiology of Aging.

[45]  M. White,et al.  Brain IRS2 Signaling Coordinates Life Span and Nutrient Homeostasis , 2007, Science.

[46]  C. Finch,et al.  Alzheimer's disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[47]  E. Cohen,et al.  The insulin paradox: aging, proteotoxicity and neurodegeneration , 2008, Nature Reviews Neuroscience.

[48]  C. Kenyon,et al.  A C. elegans mutant that lives twice as long as wild type , 1993, Nature.

[49]  George A. Carlson,et al.  The Relationship between Aβ and Memory in the Tg2576 Mouse Model of Alzheimer's Disease , 2002, The Journal of Neuroscience.

[50]  S. Lipton,et al.  Molecular pathways to neurodegeneration , 2004, Nature Medicine.

[51]  E. Masliah,et al.  Fibroblast Growth Factor 1 Regulates Signaling via the Glycogen Synthase Kinase-3β Pathway , 2002, The Journal of Biological Chemistry.

[52]  G. Arendash,et al.  Behavioral characterization of the Tg2576 transgenic model of Alzheimer's disease through 19 months , 2002, Physiology & Behavior.

[53]  C. Schnitzler,et al.  BACE2, a β-secretase homolog, cleaves at the β site and within the amyloid-β region of the amyloid-β precursor protein , 2000 .

[54]  F. Alt,et al.  SIRT1 Redistribution on Chromatin Promotes Genomic Stability but Alters Gene Expression during Aging , 2008, Cell.

[55]  Hirokazu Fukui,et al.  Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease , 2007, Proceedings of the National Academy of Sciences.

[56]  S. Younkin,et al.  The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer's disease. , 2002, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[57]  G. Glenner,et al.  Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. , 1984, Biochemical and biophysical research communications.

[58]  Richard I. Morimoto,et al.  Stress-Inducible Regulation of Heat Shock Factor 1 by the Deacetylase SIRT1 , 2009, Science.

[59]  I. Torres-Aleman,et al.  Blockade of the insulin-like growth factor I receptor in the choroid plexus originates Alzheimer's-like neuropathology in rodents: New cues into the human disease? , 2006, Neurobiology of Aging.

[60]  M. Gallagher,et al.  A specific amyloid-β protein assembly in the brain impairs memory , 2006, Nature.

[61]  Judit Villén,et al.  A Conserved MST-FOXO Signaling Pathway Mediates Oxidative-Stress Responses and Extends Life Span , 2006, Cell.

[62]  Ehud Cohen,et al.  Opposing Activities Protect Against Age-Onset Proteotoxicity , 2006, Science.

[63]  D. Selkoe.  Alzheimer Disease: Mechanistic Understanding Predicts Novel Therapies , 2004, Annals of Internal Medicine.