Pharmacologic blockade of 12/15-lipoxygenase ameliorates memory deficits, Aβ and tau neuropathology in the triple-transgenic mice

The goal of this study was to evaluate the effect of pharmacological inhibition of 12/15LO in the triple transgenic mice (3xTg), which develop amyloid plaques and tau tangles together with significant memory and learning deficits. Results demonstrated that mice receiving PD146176, a specific 12/15LO inhibitor, manifested an improvement of their memory deficits, a significant decrease in the amount of Aβ plaques and neurofibrillary tangles when compared with controls. The changes in Aβ were associated with a downregulation of the beta-secretase pathway, whereas the lower phosphorylation of tau was secondary to a selective decrease in the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK). These data suggest that 12/15LO is involved in the pathogenesis of the full spectrum of the AD-like phenotype and support the preclinical development of 12/15LO inhibitors as novel therapeutic agents for AD.