Adeno-associated virus-mediated brain delivery of 5-lipoxygenase modulates the AD-like phenotype of APP 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.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.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.The enzyme 5-lipoxygenase (5LO) catalyzes the conversion of arachidonic acid to 5-hydroxy-peroxy-eicosatetraenoic acid (5-HPETE) and subsequently to 5-hydroxy-eicosatetraenoic acid (5-HETE), which can be then metabolized into different leukotrienes [1]. The 5LO is widely expressed in the central nervous system (CNS), where it localizes mainly in neuronal cells. Its presence has been documented in various regions of the brain, including hippocampus and cortex, where significant increase in its level has been associated with aging [2-4]. Since aging is one of the strongest risk factors for developing sporadic Alzheimer's disease (AD), this pathway has been involved in its pathogenesis. To this end, 5LO immunoreactivity is increased in hippocampi of AD patients versus controls [5]; 5LO-targeted gene disruption or its pharmacologic inhibition resulted in a significant reduction of Aβ levels and deposition in the brains of the Tg2576