5-Lipoxygenase gene transfer worsens memory, amyloid, and tau brain pathologies in a mouse model of alzheimer disease

Objective: The 5-lipoxygenase (5LO) enzyme is upregulated in Alzheimer disease (AD), and its genetic absence reduces A beta levels in APP mice. However, its functional role in modulating tau neuropathology remains to be elucidated. Methods: To this end, we generated triple transgenic mice (3xTg-AD) overexpressing neuronal 5LO and investigated their phenotype. Results: Compare\d with controls, 3xTg-AD mice overexpressing 5LO manifested an exacerbation of memory deficits, plaques, and tangle pathologies. The elevation in A beta was secondary to an upregulation of gamma-secretase pathway, whereas tau hyperphosphorylation resulted from an activation of the Cdk5 kinase. In vitro study confirmed the involvement of this kinase in the 5LO-dependent tau phosphorylation, which was independent of the effect on A beta. Interpretation: Our findings highlight the novel functional role that neuronal 5LO plays in exacerbating AD-related tau pathologies. They provide critical preclinical evidence to justify testing selective 5LO inhibitors for AD treatment.ANN NEUROL 2012;72:442454.