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An aging pathway under IGF1‐R controls the TrkA to p75 neurotrophin receptor switch and amyloid‐β peptide generation
Author(s) -
Puglielli Luigi,
Costantini Claudio,
Scrable Heidi
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a981-d
Subject(s) - tropomyosin receptor kinase a , neurotrophin , low affinity nerve growth factor receptor , biology , microbiology and biotechnology , signal transduction , receptor , protein kinase b , endocrinology , medicine , genetics
Alzheimer's disease (AD) is one of the most common age‐associated disorders and is characterized by abnormal accumulation of amyloid β‐peptide (Aβ) in the form of amyloid plaques. The insulin‐like growth factor 1 (IGF1‐R) is the common regulator of lifespan in all organisms studied to date, including yeast, C. elegans, D. melanogaster, and mammals. Hypomorphic alleles of the Igf1‐r gene extend lifespan, whereas increased activation of insulin/IGF1 signaling accelerates the progression of aging. Aging of the brain is characterized by marked changes in the expression levels of neurotrophin receptors, TrkA and p75NTR. An expression pattern in which TrkA predominates in younger animals switches to one in which p75NTR predominates in older animals. This TrkA to p75NTR switch is accompanied by activation of the second messenger ceramide, stabilization of BACE1, and increased production of Aβ ( Biochem. J. 2005 ; 391 : 59 ). Here, we show that IGF1‐R is responsible for the TrkA to p75NTR switch. The signaling pathway downstream of IGF1‐R requires IRS2, PIP3, Akt, and is under the control of p44, the short isoform of p53. We also show that hyperactivation of IGF1‐R signaling in p44+/+ animals, which display an accelerated form of aging (Genes Dev. 2004;18:306), is characterized by early TrkA to p75NTR switch and increased production of Aβ in the brain. Therefore, our results implicate the general aging programming, mediated by IGF1‐R, in the molecular pathogenesis of Alzheimer's disease, the most common form of dementia in the World. Supported by N.I.H.