Docosahexaenoic acid-derived neuroprotectin D1 induces neuronal survival via secretase- and PPARγ-mediated mechanisms in Alzheimer's disease models.

Abstract

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 Aβ42 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 Aβ42 oligomeric peptide, or transfected with beta amyloid precursor protein (βAPP)(sw) (Swedish double mutation APP695(sw), K595N-M596L). We also show that NPD1 downregulates Aβ42-triggered expression of the pro-inflammatory enzyme cyclooxygenase-2 (COX-2) and of B-94 (a TNF-α-inducible pro-inflammatory element) and apoptosis in HNG cells. Moreover, NPD1 suppresses Aβ42 peptide shedding by down-regulating β-secretase-1 (BACE1) while activating the α-secretase ADAM10 and up-regulating sAPPα, thus shifting the cleavage of βAPP holoenzyme from an amyloidogenic into the non-amyloidogenic pathway. Use of the thiazolidinedione peroxisome proliferator-activated receptor gamma (PPARγ) agonist rosiglitazone, the irreversible PPARγ antagonist GW9662, and overexpressing PPARγ suggests that the NPD1-mediated down-regulation of BACE1 and Aβ42 peptide release is PPARγ-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.

• Authors: Yuhai Zhao, Frederic Calon, Carl Julien, Jeremy W Winkler, Nicos A Petasis, Walter J Lukiw, Nicolas G Bazan
• Journal: PloS one (PLoS One) Vol. 6 Issue 1 Pg. e15816 (Jan 05 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21246057 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Neuroprotective Agents
• PPAR gamma
• Peptide Fragments
• amyloid beta-protein (1-42)
• protectin D1
• Docosahexaenoic Acids
• Amyloid Precursor Protein Secretases

Topics

• Alzheimer Disease (pathology, prevention & control)
• Amyloid Precursor Protein Secretases (metabolism)
• Amyloid beta-Peptides (pharmacology)
• Amyloid beta-Protein Precursor (pharmacology)
• Animals
• Cell Survival (drug effects)
• Cells, Cultured
• Disease Models, Animal
• Docosahexaenoic Acids (physiology)
• Gene Expression Regulation
• Humans
• Mice
• Neurodegenerative Diseases (prevention & control)
• Neurons (cytology)
• Neuroprotective Agents
• PPAR gamma (metabolism)
• Peptide Fragments (pharmacology)