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 Aβ 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: Compared with controls, 3xTg‐AD mice overexpressing 5LO manifested an exacerbation of memory deficits, plaques, and tangle pathologies. The elevation in Aβ was secondary to an upregulation of γ‐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 Aβ. 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;72:442–454.