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CD40 promotion of amyloid beta production occurs via the NF‐κB pathway
Author(s) -
AitGhezala Ghania,
Volmar ClaudeHenry,
Frieling Jeremy,
Paris Daniel,
Tweed Miles,
Bakshi Pancham,
Mullan Michael
Publication year - 2007
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2007.05424.x
Subject(s) - cd40 , tumor necrosis factor alpha , amyloid precursor protein , microbiology and biotechnology , biology , receptor , neuroscience , alzheimer's disease , immunology , medicine , disease , biochemistry , cytotoxic t cell , in vitro
The CD40 receptor is a member of the tumor necrosis factor (TNF) super‐family of trans‐membrane receptors. Interaction of CD40 with its ligand CD40L mediates a broad range of immune and inflammatory responses in the periphery and in the central nervous system. Recently it has been suggested that CD40/CD40L interaction is involved in amyloid precursor protein (APP) processing and Alzheimer's disease (AD)‐like pathology in transgenic mouse models of AD. We have previously shown that pharmacologically inhibiting CD40/CD40L interaction improves memory deficits in the PSAPP AD mouse model. We have also recently shown that CD40 deficiency mitigates amyloid deposition in APPsw and PSAPP mouse models. In the present report, using human embryonic kidney cells (HEK293) over‐expressing both the APPsw mutation and CD40, we demonstrate that CD40/CD40L interaction directly increases the production of APP metabolites (Aβ 1–40, Aβ 1–42, CTFs, sAPPβ and sAPPα). The results also show that CD40/CD40L interaction affects APP processing via the NF‐κB pathway. Using NFκB inhibitors and SiRNAs to silence diverse elements of the NFκB pathway, we observe a reduction in levels of both Aβ 1–40 and Aβ 1–42. Taken together, our results further suggest that CD40L stimulation may be a key component in AD pathology and that elements of the NF‐κB pathway may be suitable targets for therapeutic approaches against AD.