Aging is the single most important risk factor for AD (Alzheimer's disease). However, the molecular events that connect normal aging to AD are mostly unknown. The abnormal accumulation of Aβ (amyloid β-peptide) in the form of senile plaques is one of the main characteristics of AD. In the present study, we show that two members of the neurotrophin receptor superfamily, TrkA (tyrosine kinase receptor A) and p75NTR (p75 neurotrophin receptor), differentially regulate the processing of APP (amyloid precursor protein): TrkA reduces, whereas p75NTR activates, β-cleavage of APP. The p75NTR-dependent effect requires NGF (nerve growth factor) binding and activation of the second messenger ceramide. We also show that normal aging activates Aβ generation in the brain by ‘switching’ from the TrkA to the p75NTR receptor system. Such an effect is abolished in p75NTR ‘knockout’ animals, and can be blocked by both caloric restriction and inhibitors of nSMase (neutral sphingomyelinase). In contrast with caloric restriction, which prevents the age-associated up-regulation of p75NTR expression, nSMase inhibitors block the activation of ceramide. When taken together, these results indicate that the p75NTR–ceramide signalling pathway activates the rate of Aβ generation in an age-dependent fashion, and provide a new target for both the understanding and the prevention of late-onset AD.

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