Medline/PubMed Citation | Related Articles in PubMed | Download to Citation Manager

Biochem. J. (2005) 391 (59–67) (Printed in Great Britain)

Enhanced Full Text

Full Text PDF

Legacy HTML

Multimedia

Other papers of interest

Add a comment

Download semantic tools

Citing articles

Article usage metrics

A TrkA-to-p75^NTR molecular switch activates amyloid b-peptide generation during aging

Claudio COSTANTINI*, Richard WEINDRUCH*, Giuliano DELLA VALLE† and Luigi PUGLIELLI*¹

*Department of Medicine, University of Wisconsin-Madison, Wm. S. Middleton Memorial Veteran's Hospital, Madison, WI 53705, U.S.A., and †Department of Biology, University of Bologna, 40126 Bologna, Italy

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 Ab (amyloid b-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 p75^NTR (p75 neurotrophin receptor), differentially regulate the processing of APP (amyloid precursor protein): TrkA reduces, whereas p75^NTR activates, b-cleavage of APP. The p75^NTR-dependent effect requires NGF (nerve growth factor) binding and activation of the second messenger ceramide. We also show that normal aging activates Ab generation in the brain by ‘switching’ from the TrkA to the p75^NTR receptor system. Such an effect is abolished in p75^NTR ‘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 p75^NTR expression, nSMase inhibitors block the activation of ceramide. When taken together, these results indicate that the p75^NTR–ceramide signalling pathway activates the rate of Ab generation in an age-dependent fashion, and provide a new target for both the understanding and the prevention of late-onset AD.

Key words: aging, Alzheimer's disease, amyloid precursor protein, ceramide, p75^NTR (p75 neurotrophin receptor), neurotrophin.

Abbreviations used: AD, Alzheimer's disease; APP, amyloid precursor protein; APP-CTF, APP C-terminal fragment; Ab, amyloid b-peptide; BACE1, b-site APP-cleaving enzyme-1; ESI–MS, electrospray ionization MS; NGF, nerve growth factor; SM, sphingomyelin; aSMase, acidic sphingomyelinase; nSMase, neutral sphingomyelinase; p75^NTR, p75 neurotrophin receptor; PS1, presenilin 1; TNF, tumour necrosis factor; TACE, TNF-converting enzyme; TrkA, tyrosine kinase receptor A; WT, wild-type.

¹To whom correspondence should be addressed (email lp1@medicine.wisc.edu).

Received 27 April 2005/7 June 2005; accepted 20 June 2005

Published as BJ Immediate Publication 20 June 2005, doi:10.1042/BJ20050700

The Biochemical Society, London ©2005

*Unofficial Impact Factors

Unofficial 2010 Impact Factor for BJ Disease calculated by dividing the number of times articles published in 2008 and 2009 were cited in 2010 (based on a search of the Web of Science^SM Thomson Reuters) by the number of articles published in 2008 and 2009.