CD40 promotion of amyloid beta production occurs via the NF‐κB pathway

Abstract

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.

Nuclear Factor-κB Regulates βAPP and β- and γ-Secretases Differently at Physiological and Supraphysiological Aβ Concentrations

“…Interestingly, the inhibition of NF-B activation reduces A␤ secretion in vitro (20 -22), and it was suggested that this could occur by interfering with ␤APP processing (22)(23)(24)(25)(26)(27). In this context, it is noteworthy that we and others previously showed that NF-B mediated the A␤-associated increase of BACE1 transcriptional activity (28,29) but to date, there is relatively little data concerning the putative control of the ␥-secretase build-up and activity or on the expression of ␤APP by NF-B; and, if so, if this control may be dependent on A␤.…”

M344 promotes nonamyloidogenic amyloid precursor protein processing while normalizing Alzheimer’s disease genes and improving memory

“…A similar trend toward nonamyloidogenic processing and anti-AD protection is also observed in significantly down-regulated genes depicted in the NanoString nCounter heat map. Among them are glycogen synthase kinase 3-β (GSK3β) (−1.4-fold, P < 0.0001), Nicastrin (NCSTN) (−3.2-fold, P < 0.0001), anterior pharynx-defective 1 (APH1) (−1.8-fold, P < 0.0001), β-site APP-Cleavage Enzyme 1 (BACE1) (−1.7-fold, P < 0.0001), BACE2 (−3.2-fold, P < 0.0001), cluster of differentiation 40 ligand (CD40L) (−1.5-fold, P < 0.01), and C-X-C Motif Chemokine Receptor 2 (CXCR2) (−2.0-fold, P < 0.0001), which are all genes hypothesized to counter AD phenotype and pathogenesis ( 37 , 39 – 41 ). In the case of late-onset AD (LOAD) genes, apolipoprotein-E-ε4 (APOEε4) is reduced (−1.8-fold, P < 0.0001), which may be therapeutically beneficial ( 21 , 42 ).…”

Flavonoids lower Alzheimer's Aß production via an NFkB dependent mechanism

“…We next investigated the effect of flavonoids on NFκB activity since flavonoids are known to display anti-inflammatory properties [16] and since we have shown previously that compounds of unrelated structure that inhibit NFκB activation can lower Aβ production by targeting the β-cleavage of APP [17, 18]. We observed that all of the flavonoids unable to significantly lower Aβ level in whole cells for the dose range tested (PD98059, taxifolin, genistein, daidzein and baicalein) were also unable to reduce NFκB activation induced by TNF±, whereas Aβ and APPsβ lowering flavonoids (kaempferol, quercetin, acacetin, apigenin and luteolin) dose dependently inhibited NFκB activation (Figure 6).…”