Modulation of lipopolysaccharide-induced memory insult, γ-secretase, and neuroinflammation in triple transgenic mice by 5-lipoxygenase

Besides amyloid and tau pathology, a constant feature of Alzheimer's disease (AD) is an intense inflammatory response, which is considered an active player in its pathogenesis. The 5-Lipoxygenase (5LO) is a proinflammatory enzyme and an endogenous modulator of AD-like phenotype in mouse models of the disease. To further understand the role of 5LO in AD pathogenesis, we exposed the triple transgenic (3 x Tg) and 3 x Tg/5LO knockout mice to lipopolysaccharide (LPS), a known inducer of neuroinflammation, and evaluated its effect on their AD-like phenotype. 3 x Tg mice treated with LPS manifested a worsening of behavior, g-secretase up-regulation, and increased neuroinflammatory responses. These effects were completely prevented in 3 x Tg mice genetically deficient for 5LO. By contrast, the absence of 5LO did not protect against increase in tau phosphorylation at specific epitopes that were mediated by the activation of the cyclin-dependent kinase 5. Our data demonstrate that the 5LO pathway affects key neuropathological features of the AD-like phenotype (behavior, abeta, microgliosis, astrocytosis) but not others (tau pathology) in the LPS-dependent neuroinflammation model. The opposite ways whereby 5LO influences the LPS-dependent effects in vivo supports the complex nature of the neuroinflammatory response in AD and its differential role in modulating amyloid and tau neuropathology. (C) 2014 Elsevier Inc. All rights reserved.