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 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.
School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America.
Yuhai
Y
Zhao
Frederic
F
Calon
Carl
C
Julien
Jeremy W
JW
Winkler
Nicos A
NA
Petasis
Walter J
WJ
Lukiw
Nicolas G
NG
Bazan
D000544:Alzheimer Disease / Q000473:pathology / Q000517:prevention & control; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000494:pharmacology; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D019636:Neurodegenerative Diseases / Q000517:prevention & control*; D009474:Neurons / Q000166:cytology*; D018696:Neuroprotective Agents; D047495:PPAR gamma / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018696:Neuroprotective Agents; D047495:PPAR gamma; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C487679:protectin D1; D004281:Docosahexaenoic Acids; D053829:Amyloid Precursor Protein Secretases
Curr Alzheimer Res. 2006 Dec;3(5):421-30
17168641
Neuroscience. 2007 Dec 5;150(2):386-95
17945434
Immunology. 2010 Feb;129(2):154-69
20561356
Neurobiol Aging. 2010 Sep;31(9):1516-31
18926603
Am J Clin Nutr. 2008 Apr;87(4):939-48
18400717
Trends Neurosci. 2010 Jul;33(7):317-25
20493564
JAMA. 2010 Nov 3;304(17):1903-11
21045096
Biomark Med. 2010 Feb;4(1):27-36
20383271
J Biol Chem. 2005 Jun 3;280(22):21453-62
15817469
J Biol Chem. 2008 Nov 14;283(46):31315-22
18801740
J Biol Chem. 2002 Aug 30;277(35):31466-73
12070143
Eur J Neurosci. 2007 Jul;26(2):381-91
17650113
Eur J Neurosci. 2007 Aug;26(4):882-9
17714184
Trends Neurosci. 2006 May;29(5):263-71
16580739
Brain Res. 1988 Jun;427(3):255-61
3401702
FASEB J. 2006 Dec;20(14):2537-9
17056761
Nat Med. 2010 Nov;16(11):1201-4
21052073
Lipids. 2001 Sep;36(9):945-59
11724467
J Clin Invest. 2005 Oct;115(10):2774-83
16151530
Brain Pathol. 2005 Apr;15(2):143-8
15912887
Curr Pharm Des. 2006;12(1):93-109
16454728
J Neurosci. 2007 Dec 26;27(52):14299-307
18160637
J Immunol. 2006 Feb 1;176(3):1848-59
16424216
J Neurosci. 2004 Dec 1;24(48):10908-17
15574741
J Biol Chem. 2003 Mar 28;278(13):11612-22
12499373
Biochem J. 2005 Nov 1;391(Pt 3):693-8
15946122
J Neurosci. 2007 Apr 18;27(16):4385-95
17442823
Neuron. 2010 Oct 21;68(2):270-81
20955934
FASEB J. 2001 Aug;15(10):1837-9
11481247
Prog Neurobiol. 2006 Jun;79(2):95-111
16904810
Proc Natl Acad Sci U S A. 2007 Aug 7;104(32):13158-63
17670935
J Neurochem. 2007 Jun;101(5):1172-84
17286590
Cell. 2010 Aug 6;142(3):356-8
20691893
Neuroreport. 2007 Jul 16;18(11):1187-91
17589324
Nat Rev Mol Cell Biol. 2007 Feb;8(2):101-12
17245412
J Biol Chem. 2010 Jun 11;285(24):18301-8
20363734
FASEB J. 2006 Jun;20(8):1162-75
16770015
FASEB J. 2006 Mar;20(3):512-4
16401644
Exp Cell Res. 2005 Mar 10;304(1):91-104
15707577
Nat Clin Pract Neurol. 2009 Mar;5(3):140-52
19262590
Annu Rev Biochem. 2008;77:289-312
18518822
Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):10858-63
16040805
J Biol Chem. 2009 Jun 26;284(26):17877-82
19403949
Nat Struct Mol Biol. 2008 Sep;15(9):924-31
19172745
J Neurosci. 2007 Mar 14;27(11):2866-75
17360908
Physiol Rev. 2001 Apr;81(2):741-66
11274343
Bioorg Med Chem Lett. 2005 Feb 1;15(3):517-22
15664804
Exp Eye Res. 2010 Jun;90(6):718-25
20230819
J Inorg Biochem. 2007 Sep;101(9):1265-9
17629564
J Neurosci Res. 2002 Nov 1;70(3):462-73
12391607
J Biol Chem. 2003 Apr 25;278(17):14677-87
12590139
PLoS One. 2010 Sep 08;5(9):e12538
20838618
Proc Natl Acad Sci U S A. 1989 Apr;86(8):2903-7
2523075
Curr Med Chem. 2009;16(6):643-51
19199928
J Biol Chem. 2003 Oct 31;278(44):43807-17
12923200
Prog Med Chem. 2004;42:1-53
15003718
Proc Natl Acad Sci U S A. 2006 Jan 10;103(2):443-8
16407166
Free Radic Biol Med. 2005 Jun 15;38(12):1604-13
15917189
J Neurosci. 2005 Mar 23;25(12):3032-40
15788759
Proc Natl Acad Sci U S A. 2004 Jun 1;101(22):8491-6
15152078
Neuron. 2004 Sep 2;43(5):633-45
15339646
J Biol Chem. 2007 Dec 21;282(51):37006-15
17965419
Neuron. 2003 Jul 31;39(3):409-21
12895417
J Biol Chem. 1996 Apr 12;271(15):8966-70
8621541
J Biol Chem. 2008 Jul 18;283(29):19927-35
18490445
Nature. 2007 Jun 14;447(7146):869-74
17568749
Nature. 2004 Aug 5;430(7000):631-9
15295589
Neurobiol Dis. 2006 Sep;23(3):563-72
16765602