Our results suggest that decreases in BACE1 may be the cause for Ab reduction. A reason for these conflicting reports may be that cell models and culture conditions used varied; in our study, we used HNG cells transiently over-expressing bAPPsw while previous reports employed cell lines using stable bAPP expression. Similar to the model of Sastre et al., our cells underwent increases in ab overproduction. Excessive Ab causes inflammatory responses in both neuronal and glial cells. Since inflammatory signaling plays a role in AD pathogenesis, we believe HNG cell cultures are a valuable model for Ab42 -mediated cellular actions. The fact that comparable results of our study were obtained at a much lower drug concentration underscores the highly sensitive nature of HNG cells after bAPP transfection. It is still possible that PPARc may repress BACE1 by antagonizing activities of other transcription factors that promote BACE1 expression, such as STAT1, NF-kB and AP1. It is noteworthy that BACE1 expression in HNG cells was increased after bAPP over-expression. The fact that PPARc did not affect the levels of sAPPa and CTFa besides PPARc antagonist being unable to reverse NPD1-elicited increase in these fragments, clearly show that PPARc is not essential for NPD1’s regulation on the nonamyloidogenic pathway. Lomitapide Mesylate Further analysis of ADAM10 showed no change occurring in ADAM10 following PPARc activation, nor did PPARc antagonists affect NPD1-enhanced expression of Mepiroxol mature ADAM10. Therefore, modulation by NPD1 of a-secretase and bAPP processing are independent of PPARc. ADAM10 is synthesized as an inactive zymogene and is processed to its mature form by cleavage of the pro-domain by pro-protein convertases, such as furin and PC7. Other evidence also demonstrated that protein kinase C and mitogen-activated protein kinase, particularly extracellular signal-regulated kinases, are involved in regulation of a-secretase activity. No cross-talk between the PCs and PKC or MAP kinases has been reported. Since in our study only the mature ADAM10 was increased, it is likely that the PPCs are implicated in NPD1 actions. PPARc antagonist GW9662 also failed to reverse the antiapoptotic effect of NPD1, indicating that PPARc is not implicated in NPD1 anti-apoptotic bioactivity. NPD1 attained this neuroprotection at a concentration of 50 nM, at which its PPARc activity is far from physiologically relevant in the in vitro system. Other mechanisms have been proposed to explain DHA’s anti-apoptotic and anti-inflammatory effects, including maintenance of plasma membrane integrity, activation of Akt signaling, and conversion into other derivatives. These findings also provide clues for NPD1’s potential targets. NPD1 inhibits NFkB activation and COX-2 expression in brain ischemia-reperfusion, while Ab peptide-induced apoptosis is associated with ERK and p38 MAPK-NF-kB mediated COX-2 up-regulation. Neuroprotection mediated by NPD1 may further involve components of signaling pathways upstream of NF-kB activation and DNA-binding. Our results provide compelling evidence that NPD1 is endowed with strong anti-inflammatory, anti-amyloidogenic, and antiapoptotic bioactivities in HNG cells upon exposure to Ab42 oligomers, or in HNG cells over-expressing bAPPsw. These results suggest that NPD1’s anti-amyloidogenic effects are mediated in part through activation of the PPARc receptor, while NPD1’s stimulation of non-amyloidogenic pathways is PPARc-independent. Suggested sites of NPD1 actions are schematically presented in Figure 11. NPD1 stimulation of ADAM10 coupled to suppression of BACE1-mediated Ab42 secretion clearly warrants further study, as these dual secretase-mediated pathways may provide effective combinatorial or multi-target approaches in the clinical management of the AD process. Tau is an axonally located, microtubule-associated protein that is encoded by a single gene and predominantly expressed in neurons. Tau mRNA transcripts can be spliced alternatively, and the expression of tau-isoforms is developmentally regulated and varies between species.