P44 transgenic mice have an early and dramatic increase in Aβ levels inthe brain: a possible role of IGF-1 signaling in the regulation of Aβproduction during aging.

Aging is the single most important risk factor for late-onset Alzheimer’s disease (LOAD), which represents 95 to 97% of all cases of AD. Our group has recently shown that normal aging of the brain is accompanied by a progressive activation of the second messenger ceramide, which is responsible for the molecular stabilization of BACE1 and consequent increase in β cleavage of the amyloid precursor protein (APP). Such event is triggered by an age-dependent up-regulation of p75NTR expression. Here, we have analyzed p75NTR/TrkA signaling, ceramide metabolism, APP processing, and Aβ generation in mice transgenic for p44, the short isoform of p53 (Genes and Development; 2004: 306). P44+/+ mice represent a model of early and accelerated aging associated with a marked over-activation of the insulin-like growth factor 1 (IGF-1) signaling pathway, an evolutionary conserved regulator of lifespan. P44+/+ mice brain revealed a dramatic increase in the expression levels of p75NTR, which was paralleled by decreased levels of TrkA. The expression levels of both p75NTR and TrkA observed in 1-month-old p44+/+ mice were similar to those observed in 30-month-old control animals. The marked increase in p75NTR expression was paralleled by similar changes in the levels of ceramide, BACE1, and β-APP-CTF. Finally, Aβ levels were found to be significantly higher in p44+/+ mice, when compared to age-matched control animals. Inhibition of ceramide production reduced the steady-state levels of both BACE1 and β-APP-CTF indicating a direct effect on the rate of β cleavage of APP. We conclude that the increased production of Aβ in p44+/+ mice is caused by the increased activation of the p75NTR-ceramide signaling pathway down-stream IGF-1 signaling.