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

作者：Chu Jin; Giannopoulos Phillip F; Ceballos Diaz Carolina; Golde Todd E; Pratico Domenico^*

来源：Molecular Neurodegeneration, 2012, 7: 1.

DOI：10.1186/1750-1326-7-1

• Alzheimer%26apos
• s disease
• animal model
• amyloid beta
• 5-Lipoxygenase

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%26apos;s disease (AD), and that its genetic absence results in a reduction of Amyloid beta (A beta) 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. %26lt;br%26gt;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 A beta peptides and deposition, no change in the steady state levels of amyloid-beta precursor protein (APP), BACE-1 or ADAM-10, but a significant increase in PS1, nicastrin, and Pen-2, three major components of the gamma-secretase complex. Additional data indicate that the transcription factor CREB was elevated and so were the mRNA levels for PS1, nicastrin and Pen-2. %26lt;br%26gt;Conclusions: These data demonstrate that neuronal 5LO plays a functional role in the pathogenesis of AD-like amyloidotic phenotype by modulating the gamma-secretase pathway. They support the hypothesis that this enzyme is a novel therapeutic target for the treatment and prevention of AD.

• 出版日期2012-1-5