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A TrkA-to-p75NTR molecular switch activates amyloid beta-peptide generation during aging.

ABSTRACT: 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 Abeta (amyloid beta-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, beta-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 Abeta 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 Abeta generation in an age-dependent fashion, and provide a new target for both the understanding and the prevention of late-onset AD.

SUBMITTER: Costantini C

PROVIDER: S-EPMC1237139 | biostudies-literature | 2005 Oct

REPOSITORIES: biostudies-literature

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A TrkA-to-p75NTR molecular switch activates amyloid beta-peptide generation during aging.

Costantini Claudio C Weindruch Richard R Della Valle Giuliano G Puglielli Luigi L

The Biochemical journal 20051001 Pt 1

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 Abeta (amyloid beta-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 (a ...[more]

PMID: 15966860

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Project description:The topology and trafficking of receptors play a key role in their signalling capability. Indeed, receptor function is related to the microenvironment inside the cell, where specific signalling molecules are compartmentalized. The response to NGF (nerve growth factor) is strongly dependent on the trafficking of its receptor, TrkA. However, information is still scarce about the role of the cellular localization of the TrkA co-receptor, p75NTR (where NTR is neurotrophin receptor), following stimulation by NGF. It has been shown that these two receptors play a key role in epithelial tissue and in epithelial-derived tumours, where the microenvironment at the plasma membrane is defined by the presence of tight junctions. Indeed, in thyroid carcinomas, rearrangements of TrkA are frequently found, which produce TrkA mutants that are localized exclusively in the cytoplasm. We used a thyroid cellular model in which it was possible to dissect the trafficking of the two NGF receptors upon neurotrophin stimulation. In FRT (Fischer rat thyroid) cells, endogenous TrkA is localized exclusively on the basolateral surface, while transfected p75NTR is selectively distributed on the apical membrane. This cellular system enabled us to selectively stimulate either p75NTR or TrkA and to analyse the role of receptor trafficking in their signalling capability. We found that, after binding to NGF, p75NTR was co-immunoprecipitated with TrkA and was transcytosed at the basolateral membrane. We showed that the TrkA-p75NTR interaction is necessary for this relocation of p75NTR to the basolateral side. Interestingly, TrkA-specific stimulation by basolateral NGF loading also induced the TrkA-p75NTR interaction and subsequent p75NTR transcytosis at the basolateral surface. Moreover, specific stimulation of p75NTR by NGF activated TrkA and the MAPK (mitogen-activated protein kinase) pathway. Our data indicate that TrkA regulates the subcellular localization of p75NTR upon stimulation with neurotrophins, thus affecting the topology of the signal transduction molecules, driving the activation of a specific signal transduction pathway.

Dataset Information

A TrkA-to-p75NTR molecular switch activates amyloid beta-peptide generation during aging.

Publications

A TrkA-to-p75NTR molecular switch activates amyloid beta-peptide generation during aging.

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