12/15-LIPOXYGENASE INHIBITION REVERSES COGNITIVE IMPAIRMENT, AMYLOIDOSIS, TAU AND SYNAPTIC PATHOLOGY BY STIMULATING AUTOPHAGY IN THE BRAIN OF AGED 3XTG MICE

Abstract

Alzheimer's disease (AD) is the leading cause of dementia, afflicting 5 million Americans and costing over 200 billion dollars per year. The mechanisms involved in AD pathogenesis are still poorly understood. Moreover, no therapy is available to cure AD or to slow down its progression. The study of new pathways involved in AD pathogenesis is necessary to develop new therapeutic targets. The 12/15-lipoxygenase enzymatic pathway (12/15-LO) is upregulated in postmortem brain tissues and cerebrospinal fluid of AD patients. Its genetic absence or pharmacological inhibition prevents the development of the AD-like phenotype in transgenic mouse models of the disease. However, whether targeting pharmacologically this pathway after the neuropathological lesions and behavioral impairments are well established could be a viable therapeutic strategy against AD remain to be investigated. To this end, 12-month-old triple transgenic mice (3xTg) and their appropriate wild type controls were randomized to receive a specific and selective pharmacological inhibitor of 12/15-LO, PD146176, or placebo. After 3 months, when the animals were 15-month-old, treated and untreated groups were assessed for the effects of the drug on their behavioral impairments and neuropathology. While 15-month-old 3xTg mice on placebo by the end of the study showed a worsening of their memory and learning abilities, as assessed by the fear conditioning paradigms, mice at the same age receiving the PD146176 performed better than baseline in the same test. Compared with placebo, treated mice had significantly less Abeta levels and deposition, improved tau pathology as well as markers of synaptic integrity. Additionally, the same PD146176 treated animals showed a significant upregulation of autophagy markers, suggesting an involvement of this pathway in the pharmacological effect. In vitro experiments demonstrated that 12/15-LO effect on tau metabolism is mediated by modulating neuronal autophagy system. These studies provide new insights into the disease-modifying action of pharmacological inhibiting 12/15-LO as a viable therapeutic approach for AD treatment. They represent the successful completion of the preclinical studies for the development of this class of drug as clinically applicable therapy for the disease.