While we cannot exclude the possibility that glial cells are providing some neuroprotective ‘shielding’, both neuronal and glial cells release cytokines when exposed to Ab42 that, in turn, activate more microglia and astrocytes that reinforce pathogenic signaling. NPD1 is anti-inflammatory and promotes inflammatory resolution. In HNG cell models of Ab42 toxicity, microarray analysis and Western blot analysis Chlorhexidine hydrochloride revealed down-regulation of pro-inflammatory genes, suggesting NPD1’s anti-inflammatory bioactivity targets, in part, this gene family. These effects are persistent, as shown by time-course Western blot analysis in which protein expression was examined up to 12 h after treatment by Ab42 and NPD1. Although counteracting Ab42-induced neurotoxicity is a promising strategy for AD treatment, curbing excessive Ab42 release during neurodegeneration is also desirable. DHA could lower Ab42 load in the CNS by stimulating non-amyloidogenic bAPP processing, reducing PS1 expression, or by increasing the expression of the sortilin receptor, SorLA/LR11. In contrast to a previous Lomitapide Mesylate report by Green et al. that suggested that Ab peptide reductions in whole brain homogenates of 3xTg AD after dietary supplementation of DHA were the result of decreases in the steady state levels of PS1, our experiments in primary HNG cells showed no effects of NPD1 on PS1 levels, but a significant increase in ADAM10 coupled to a decrease in BACE1. These later observations were further confirmed by both activity assays and siRNA knockdown. NPD1 reduces Ab42 levels released from HNG cells over-expressing APPsw in a dose-dependent manner. Our examination of other bAPP fragments revealed after NPD1 addition, a reduction in the b-secretase products sAPPbsw and CTFb occurred, along with an increase in a-secretase products sAPPa and CTFa, while levels of bAPP expression remained unchanged in response to NPD1. Hence these abundance- and activity-based assays indicate a shift by NPD1 in bAPP processing from the amyloidogenic to non-amyloidogenic pathway. Previously sAPPa has been found to promote NPD1 biosynthesis from DHA, while in the present study NPD1 works to stimulate sAPPa secretion, creating positive feedback and neurotrophic reinforcement. Secreted sAPPa’s beneficial effects include enhanced learning, memory and neurotrophic properties. NPD1 further down-regulated the b-secretase BACE1 and activated ADAM10, a putative a-secretase. Our ADAM10 siRNA knockdown and BACE1 over-expression-activity experiments confirmed that ADAM10 and BACE1 are required in NPD1’s regulation of bAPP. NPD1 therefore appears to function favorably in both of these competing bAPP processing events. PPARc activation leads to anti-inflammatory, anti-amyloidogenic actions and anti-apoptotic bioactivity, as does NPD1. Some fatty acids are natural ligands for PPARc, which have a predilection for binding polyunsaturated fatty acids. Our hypothesis that NPD1 is a PPARc activator was confirmed by results from both human adipogenesis and cell-basedtransactivation assay. NPD1 may activate PPARc via direct binding or other interactive mechanisms. Analysis of bAPP-derived fragments revealed that PPARc does play a role in the NPD1-mediated suppression of Ab production. Over-expressing PPARc or incubation with a PPARc agonist led to reductions in Ab, sAPPb and CTFb similar to that with NPD1 treatment, while a PPARc antagonist abrogated these reductions. Activation of PPARc signaling is further confirmed by the observation that PPARc activity decreased BACE1 levels, and a PPARc antagonist overturned this decrease. Thus, the antiamyloidogenic bioactivity of NPD1 is associated with activation of the PPARc and the subsequent BACE1 down-regulation. The difference between the bioactivity of NPD1 concentrations for anti-apoptotic and anti-amyloidogenic activities may be due to the different cell models used and/or related mechanisms. Although Ab-lowering effects of PPARc have been reported, the molecular mechanism of this action remains unclear.