Adeno-associated virus-mediated brain delivery of 5-lipoxygenase modulates the AD-like phenotype of APP mice.
BACKGROUND
The 5-lipoxygenase (5LO) enzymatic pathway is widely distributed within the central nervous system. Previous works showed that this protein is up-regulated in Alzheimer's disease (AD), and that its genetic absence results in a reduction of Amyloid beta (Aβ) levels in the Tg2576 mice.Here by employing an adeno-associated viral (AAV) vector system to over-express 5LO in the same mouse model, we examined its contribution to their cognitive impairments and brain AD-like amyloid pathology.


RESULTS
Our results showed that compared with controls, 5LO-targeted gene brain over-expression in Tg2576 mice results in significant memory deficits. On the other hand, brain tissues had a significant elevation in the levels of Aβ peptides and deposition, no change in the steady state levels of amyloid-β precursor protein (APP), BACE-1 or ADAM-10, but a significant increase in PS1, nicastrin, and Pen-2, three major components of the γ-secretase complex. Additional data indicate that the transcription factor CREB was elevated and so were the mRNA levels for PS1, nicastrin and Pen-2.


CONCLUSIONS
These data demonstrate that neuronal 5LO plays a functional role in the pathogenesis of AD-like amyloidotic phenotype by modulating the γ-secretase pathway. They support the hypothesis that this enzyme is a novel therapeutic target for the treatment and prevention of AD.
Department of Pharmacology, Temple University, Philadelphia, PA 19140, USA.
Jin
J
Chu
Phillip F
PF
Giannopoulos
Carolina
C
Ceballos-Diaz
Todd E
TE
Golde
Domenico
D
Pratico
D000544:Alzheimer Disease / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D008568:Memory / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D010641:Phenotype
D016564:Amyloid beta-Protein Precursor; D001094:Arachidonate 5-Lipoxygenase; D053829:Amyloid Precursor Protein Secretases