An aging pathway controls the TrkA to p75NTR receptor switch and amyloid β-peptide generation

Claudio Costantini, Heidi Scrable, Luigi Puglielli

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

Aging of the brain is characterized by marked changes in the expression levels of the 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 β-site amyloid precursor protein-cleaving enzyme-1 (BACE1), and increased production of amyloid β-peptide (Aβ). Here, we show that the insulin-like growth factor-1 receptor (IGF1-R), the common regulator of lifespan and age-related events in many different organisms, is responsible for the TrkA-to-p75NTR switch in both human neuroblastoma cell lines and primary neurons from mouse brain. The signaling pathway that controls the level of TrkA and p75NTR downstream of the IGF1-R requires IRS2, PIP3/Akt, and is under the control of PTEN and p44, the short isoform of p53. We also show that hyperactivation of IGF1-R signaling in p44 transgenic animals, which show an accelerated form of aging, is characterized by early TrkA-to-p75NTR switch and increased production of Aβ in the brain.

Original languageEnglish (US)
Pages (from-to)1997-2006
Number of pages10
JournalEMBO Journal
Volume25
Issue number9
DOIs
StatePublished - May 3 2006
Externally publishedYes

Fingerprint

Somatomedin Receptors
Amyloid
Somatomedins
Aging of materials
Switches
Brain
Peptides
Animals
Nerve Growth Factor Receptors
Genetically Modified Animals
Amyloid beta-Protein Precursor
Ceramides
Second Messenger Systems
Neuroblastoma
Protein Isoforms
Neurons
Cell Line
Stabilization
Chemical activation
Cells

Keywords

  • Alzheimer's disease
  • Amyloid β-peptide
  • Ceramide
  • IGF1-R
  • p75

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

An aging pathway controls the TrkA to p75NTR receptor switch and amyloid β-peptide generation. / Costantini, Claudio; Scrable, Heidi; Puglielli, Luigi.

In: EMBO Journal, Vol. 25, No. 9, 03.05.2006, p. 1997-2006.

Research output: Contribution to journalArticle

Costantini, Claudio ; Scrable, Heidi ; Puglielli, Luigi. / An aging pathway controls the TrkA to p75NTR receptor switch and amyloid β-peptide generation. In: EMBO Journal. 2006 ; Vol. 25, No. 9. pp. 1997-2006.
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