Amelioration of the Alzheimer's disease phenotype by absence of 12/15-lipoxygenase.
BACKGROUND
Alzheimer's disease (AD) is a chronic neurodegenerative disorder whose initiating events are not known. Increasing evidence suggests that oxidative stress and inflammation play a role in its pathogenesis. 12/15 Lipoxygenase (12/15LO) by oxidizing polyunsaturated fatty acids forms hydroperoxyacids, which are potent pro-oxidants and inflammatory mediators. Previously, we reported that this metabolic pathway is increased in AD.


METHODS
Here we explore the effect of genetic deletion of 12/15LO on the AD-like phenotype of the tg2576 transgenic mice.


RESULTS
Genetic absence of this enzyme results in a significant reduction in amyloid-β (Aβ) production and deposition and an improvement of cognitive deficits. In vivo and in vitro studies show that the effect of this enzymatic pathway on amyloidosis is mediated by modulation of Aβ precursor protein processing via the β secretase (BACE) proteolytic cascade, which ultimately results in altered formation of Aβ peptides.


CONCLUSIONS
Our findings support the novel hypothesis that blockade of 12/15LO in the central nervous system by modulating BACE proteolytic pathway could be an effective therapy for prevention or treatment of AD.
Yang
Hengxuan
H
Department of Pharmacology, Temple University, School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Zhuo
Jia-Min
JM
Chu
Jin
J
Chinnici
Cinzia
C
Praticò
Domenico
D
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics* / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002461:Cell Line, Transformed; D003072:Cognition Disorders / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
C475064:12-15-lipoxygenase; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D053829:Amyloid Precursor Protein Secretases