Adeno-associated virus-mediated brain delivery of 5-lipoxygenase modulates the AD-like phenotype of APP mice

• DOI: 10.1186/1750-1326-7-1
• Publication Date: 2012-01-06T07:58:30Z
• Authors: Jin Chu; Phillip F Giannop...; Carolina Ceballos...; Todd E Golde; Domenico Pratico
• Keywords: 0301 basic medicine; Genetic Vectors; Clinical Neurology; Mice, Transgenic; Cellular and Molecular Neuroscience; Amyloid beta-Protein Precursor; Mice; 03 medical and health sciences; Alzheimer Disease; Memory; Animals; Humans; RC346-429; Molecular Biology; 5-Lipoxygenase; Neurons; Arachidonate 5-Lipoxygenase; animal model; RC952-954.6; Brain; Alzheimer's disease; Dependovirus; 3. Good health; amyloid beta; Disease Models, Animal; Phenotype; Geriatrics; Female; Neurology. Diseases of the nervous system; Amyloid Precursor Protein Secretases; Research Article

AbstractBackgroundThe 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.ResultsOur 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.ConclusionsThese 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.