Docosahexaenoic Acid-Derived Neuroprotectin D1 Induces Neuronal Survival via Secretase- and PPARγ-Mediated Mechanisms in Alzheimer's Disease Models

Neuroprotectin D1 (NPD1) is a stereoselective mediator derived from the omega-3 essential fatty acid docosahexaenoic acid (DHA) with potent inflammatory resolving and neuroprotective bioactivity. NPD1 reduces A beta 42 peptide release from aging human brain cells and is severely depleted in Alzheimer's disease (AD) brain. Here we further characterize the mechanism of NPD1's neurogenic actions using 3xTg-AD mouse models and human neuronal-glial (HNG) cells in primary culture, either challenged with A beta 42 oligomeric peptide, or transfected with beta amyloid precursor protein (beta APP)(sw) (Swedish double mutation APP695(sw), K595N-M596L). We also show that NPD1 downregulates A beta 42-triggered expression of the pro-inflammatory enzyme cyclooxygenase-2 (COX-2) and of B-94 (a TNF-alpha-inducible pro-inflammatory element) and apoptosis in HNG cells. Moreover, NPD1 suppresses A beta 42 peptide shedding by down-regulating beta-secretase-1 (BACE1) while activating the alpha-secretase ADAM10 and up-regulating sAPP alpha, thus shifting the cleavage of beta APP holoenzyme from an amyloidogenic into the non-amyloidogenic pathway. Use of the thiazolidinedione peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist rosiglitazone, the irreversible PPAR gamma antagonist GW9662, and overexpressing PPAR gamma suggests that the NPD1-mediated down-regulation of BACE1 and A beta 42 peptide release is PPAR gamma-dependent. In conclusion, NPD1 bioactivity potently down regulates inflammatory signaling, amyloidogenic APP cleavage and apoptosis, underscoring the potential of this lipid mediator to rescue human brain cells in early stages of neurodegenerations.