CD40 promotion of amyloid beta production occurs via the NF-kappaB pathway.
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 (Abeta 1-40, Abeta 1-42, CTFs, sAPPbeta and sAPPalpha). The results also show that CD40/CD40L interaction affects APP processing via the NF-kappaB pathway. Using NFkappaB inhibitors and SiRNAs to silence diverse elements of the NFkappaB pathway, we observe a reduction in levels of both Abeta 1-40 and Abeta 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-kappaB pathway may be suitable targets for therapeutic approaches against AD.
Ait-Ghezala
Ghania
G
The Roskamp Institute, Sarasota, FL 34243, USA. gaitghezala@rfdn.org
Volmar
Claude-Henry
CH
Frieling
Jeremy
J
Paris
Daniel
D
Tweed
Miles
M
Bakshi
Pancham
P
Mullan
Michael
M
D016229:Amyloid beta-Peptides / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism*; D002461:Cell Line, Transformed; D015232:Dinoprostone / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D009154:Mutation / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection
D016229:Amyloid beta-Peptides; D019013:CD40 Antigens; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; D015232:Dinoprostone