Alzheimer's disease is a devastating, irreversible and progressive neurodegenerative disease with unknown etiology and no effective cure. A dietary factor, saturated fatty acid palmitate, induces amyloidogenesis in primary rat neurons mediated by astrocytes, however, the molecular mechanisms by which conditioned media from palmitate-treated astrocytes upregulates amyloid beta level by BACE1 and gamma-secretase in neurons are unknown. The present study demonstrates that upregulated serine palmitoyltransferase in the astrocytes increased ceramide levels, leading to the release of cytokines, namely TNFalpha and IL-1beta, which mediated the activation of neutral and acidic sphingomyelinase (SMase) to propagate the deleterious effects of palmitate. Activated SMases elevated ceramide levels and in turn enhanced BACE1 level in the neurons. Thus, this study suggests that tight regulation of ceramide production may be an important therapeutic approach to modulating BACE1 level. Moreover, this study identified a signaling pathway in which the condition media from palmitate-treated astrocytes rapidly elevates calcium level in the neurons, and subsequently calpain activity, a calcium-dependent protease, resulting in enhanced p25/Cdk5 activity, and in turn the phosphorylation and activation of STAT3, a transcription factor. STAT3 transcriptionally regulates the expression of both BACE1 and presenilin-1, a catalytic subunit of gamma-secretase, in primary neurons, suggesting that STAT3 is an important potential therapeutic target to control AD pathogenesis. Inflammatory response has been strongly implicated in numerous diseases, including AD, and IL-1beta has been indicated in the pathogenesis of AD. Elevated IL-1beta in conditioned media released by palmitate-treated astrocytes activates the SMases-ceramide-BACE1 pathway in primary neurons, enhances calcium level, and triggers the calcium-calpain-Cdk5/p25-STAT3 signaling cascade, leading to the upregulation of BACE1 and presenilin-1 in neurons. However, little is known about the molecular mechanisms that initiate the generation of IL-1beta in astrocytes upon palmitate treatment. Here we investigated and identified that palmitate induced the activation of the IPAF-ASC inflammasome in astrocytes leading to the maturation of IL-1beta, thereby indicating that not only pathogen-related factors can activate IPAF-ASC inflammasome. The expression of IPAF was found to be regulated by transcription factor CREB. Moreover, downregulating IPAF in astrocytes decreased IL-1beta secretion from the astrocytes and reduced the generation of amyloid beta 42 by primary neurons. Furthermore, the expression levels of IPAF and ASC were found significantly elevated in a subgroup of sporadic AD patients, suggesting the involvement of the IPAF-ASC inflammasome in the inflammatory response associated with AD, and a potential role of IPAF-ASC as a therapeutic target to control AD.
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