IGF-R, the common regulator of life span, acts upstream of p75NTR in the regulation of Aβ generation during aging.

One of the main characteristics of Alzheimer’s disease is the abnormal accumulation of amyloid β-peptide (Aβ) in the form of senile (or amyloid) plaques. Even though aging is the single most important risk factor for Alzheimer’s disease (AD), the molecular events that connect normal aging to AD are unknown. We have recently shown that aging is characterized by a TrkA to p75NTR switch that activates the rate of Aβ generation through the second messenger ceramide. Here we have used neuroblastoma cell lines, primary neurons, and p44+/+ mice to identify the up-stream event that controls the TrkA to p75NTR transition. Our results indicate that the insulin-like growth factor receptor (IGF-R) controls the rate of Aβ generation by acting up-stream p75NTR/TrkA. Indeed, IGF-R signaling activates p75NTR expression while down-regulating TrkA; such effect is accompanied by activation of ceramide, increased expression of BACE1, and increased β cleavage of APP. Both antisense oligonucleotides and siRNA against IGF-R successfully blocked the activation of the p75NTR-ceramide signaling pathway with consequent reduction in β cleavage of APP. Similar results were obtained by over-expressing the phosphate and tensin homologue deleted on chromosome ten (PTEN), which blocks IGF-R signaling. In contrast, over-expression of p44, which releases the block of IGF-R signaling mediated by PTEN, was followed by up-regulation of p75NTR, down-regulation of TrkA, and consequent activation of BACE1-mediated cleavage of APP. Finally, pharmacologic inhibiton of IGF-R signaling, down-stream phosphatidyilinositol triphosphate (PIP3) successfully blocked the effects induced by IGF1. In conclusion, our results show that IGF-R, the common regulator of lifespan, controls the rate of Aβ generation during aging by switching neurotrophin signaling from TrkA to p75NTR, and consequent activation of the second messenger ceramide.