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

Yuhai Zhao,Jeremy W Winkler,Nicos A Petasis,Walter J Lukiw,Frederic Calon,Nicolas G Bazan,Carl Julien,Mark A Smith

doi:10.1371/journal.pone.0015816

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 APP695sw, 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.

Highlights

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment and, at the cellular level, by synaptic damage, intracellular neurofibrillary tangles and beta-amyloid precursor protein processing dysfunction that leads to overabundance of the 42 amino acid amyloid-beta (Ab42) peptide
Ab42 peptides are generated from beta-amyloid precursor protein (bAPP) via tandem cleavage by beta- and gamma- (b- and c-) secretases; alternatively an alpha-secretase distintegrin and metalloproteinase 10 (ADAM10) cleaves bAPP to yield a soluble form of bAPP, sAPPa, via the non-amyloidogenic or neurotrophic pathway
Omega-3 essential fatty acid-rich diets are associated with a trend in reduced risk for MCI and with MCI conversion to AD, whereas Docosahexaenoic acid (DHA) has been shown to be beneficial in transgenic AD models [8,10,11,16,50]

Summary

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment and, at the cellular level, by synaptic damage, intracellular neurofibrillary tangles and beta-amyloid precursor protein (bAPP) processing dysfunction that leads to overabundance of the 42 amino acid amyloid-beta (Ab42) peptide. Docosahexaenoic acid (DHA; C22:6), an omega-3 essential fatty acid family member, is enriched in central nervous system (CNS), synaptic and other cellular membranes as an acyl chain of membrane phospholipids. DHA is involved in the building and function of the CNS, as well as synaptogenesis, cognition, neuroprotection, synaptic function and vision [7,8,9,10]. Deficiencies in DHA biosynthesis by the liver correlate with cognitive impairment in AD patients [13], supporting the significance of the liver supply of DHA to the CNS in neurodegenerative diseases [13,14]. In AD transgenic mice dietary DHA restores cerebral blood volume, reduces Ab deposition, and ameliorates Ab pathology [15,16]

Methods

Results

Conclusion