An aging pathway controls the TrkA to p75^NTR receptor switch and amyloid β-peptide generation

Aging of the brain is characterized by marked changes in the expression levels of the neurotrophin receptors, TrkA and p75^NTR. An expression pattern in which TrkA predominates in younger animals switches to one in which p75^NTR predominates in older animals. This TrkA-to-p75^NTR 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-p75^NTR switch in both human neuroblastoma cell lines and primary neurons from mouse brain. The signaling pathway that controls the level of TrkA and p75^NTR 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-p75^NTR switch and increased production of Aβ in the brain.