title: Neuroprotectin D1 induces neuronal survival and downregulation of amyloidogenic processing in Alzheimer's disease cellular models.
abstract: The mediator neuroprotectin D1 (NPD1) is an enzymatic derivative of the omega-3 essential fatty acid docosahexaenoic acid. NPD1 stereoselectively and specifically binds to human retinal pigment epithelium (RPE) cells and neutrophils. In turn, this lipid mediator induces dephosphorylation of Bcl-x(L) in a PP2A-dependent manner and induces PI3K/Akt and mTOR/p70S6K pathways leading to RPE cell survival during oxidative stress-induced apoptosis. As a proof of principle of its systemic in vivo bioactivity, NPD1 attenuates laser-induced choroidal neovascularization in mice. Using human neural cells transfected with amyloid precursor protein (APP)sw (Swedish double mutation APP695sw, K595N, M596L), NPD1 was shown to regulate secretase-mediated production of Aβ peptide, downregulates pro-inflammatory gene expression, and promotes cell survival. In human neural cells overexpressing beta-amyloid precursor protein (βAPP), the lipid mediator suppressed Aβ42 shedding by downregulating β-secretase (BACE1) while activating the α-secretase (ADAM10), thus shifting the βAPP cleavage from the noxious amyloidogenic pathway into a non-amyloidogenic, neurotrophic pathway. Furthermore, downregulation of Aβ42 peptide release by NPD1 may be dependent upon PPARγ activation. In conclusion, NPD1 exhibits anti-inflammatory, anti-amyloidogenic, and anti-apoptotic bioactivities in human neural cells in part via PPARγ signaling and through the targeting of α- and β-secretase systems.
authors: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, 2020 Gravier Street, Suite D, New Orleans, LA 70112, USA.
authors: David T
authors: DT
authors: Stark
authors: Nicolas G
authors: NG
authors: Bazan
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D000682:Amyloid / Q000378:metabolism*; D002470:Cell Survival; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism / Q000473:pathology*
chemical_list: D000682:Amyloid; C487679:protectin D1; D004281:Docosahexaenoic Acids