Caloric restriction prevents the age-associated activation of amyloidβ-peptide generation induced by the p75NTR-ceramide signaling pathway

Late-onset Alzheimer’s disease (AD) represents 95 to 97% of all cases of AD. The age-associated increase in the prevalence of late-onset AD does not reach a plateau. Our group has recently shown that the second messenger ceramide regulates the rate of amyloid β-peptide (Aβ) generation by affecting the molecular stability of BACE1 (J. Biol. Chem. 2003). Here we explored the role of ceramide during aging by analyzing sphingomyelin/ceramide metabolism, amyloid precursor protein (APP) processing, and Aβ generation in the brain of normally aged mice. We found that aging of the brain is accompanied by a progressive activation of neutral sphingomyelinase (nSMase) that leads to increased production of ceramide. The activation of nSMase is induced by “re-expression” of the neurotrophin receptor p75NTR. We also found that aging is accompanied by increased levels of the β-secretase BACE1 and by increased β-cleavage of APP. To further confirm the role of aging on the above events, normally aged mice were restricted in their food intake, a condition that has been proved to extend the maximum-life-span and to delay many biological changes that are associated with aging. We found that caloric restriction down-regulates both the expression of p75NTR and the production of ceramide, blocking the increase of BACE1 steady-state levels and Aβ generation associated with aging. We conclude that p75NTR-ceramide is a molecular link between normal aging and late-onset AD, and that caloric restriction may represent a novel dietetic approach for the prevention of AD.