Ibuprofen modulates inflammatory and autophagy-associated pathways linked to neurodegenerative pathology in APOE-context-dependent cellular models

The onset and sustenance of Alzheimers and Parkinsons is solely dependent on the driving power of the immune cytokine interleukin-1 beta (IL-1β), arising from neuronal distress and release of sAPPα, which activates microglia for synthesis and release of IL-1β driving synthesis of βAPP, Aβ plaques and synthesis and activation of MAPKp38 for phosphorylation of tau for neurofibrillary tangle formation in Alzheimers and for a-synuclein for formation of Lewy bodies in Parkinsons. As long-term use of Ibuprofen decreases the risk of both diseases, we pitted the power of Ibuprofen against that of the driving power of IL-1β. RT-PCR and Western immunoblotting were used to determine the levels of IL-1β and its downstream mRNAs and proteins in primary neurons, HMC3 cells, T98G stably transformed with APOEε3 or APOEε4 and SH-SY5Y cells expressing Amyloid Precursor Protein (SH-SYFY-APP). ICC was used to determine the autophagy levels in HMC3 cells. Ibuprofen decreased mRNA and protein levels of IL-1β and its downstream proteins, TNFα, βAPP, MAPKp38, MyD88, NFκB, and COX-2, while increasing the gene levels of synaptophysin and autophagy proteins that favor clearance especially in ApoE3 and -4 cells. Our results showing that Ibuprofen decreases the known mechanism of IL-1β to drive the synthesis of each of the aggregates diagnostic of Alzheimers and Parkinsons while simultaneously boosting autophagy for their clearance provides for a vision of one day with Ibuprofen or some more perfect foil these dread diseases may be prevented.