Estudio del efecto del ácido graso de diseño LP226 en un modelo murino transgénico de la enfermedad de Alzheimer (5XFAD)

Abstract

Introduction Alzheimer's disease (AD) is the most common neurodegenerative disorder during aging. However, no effective therapy is available for its treatment yet. The high incidence of AD in elderly individuals, together with the progressive increase of the current life expectancy and the progressive aging of the population, make this disease one of the most important socio-sanitary problems of our time. However, the etiology of this disease (probably multifactorial) remains unknown. Recently, the development of the disease has been linked to lipid alterations, such as increased levels of cholesterol and sphingomyelin, or a decrease in levels of omega-3 polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA). In this sense, treatments with DHA in animal models of AD have been very promising. However, DHA clinical trials in humans affected by AD have been inconclusive regarding its pharmacological efficacy. It is noteworthy the importance of natural hydroxylated derivatives of DHA, such as neuroprotectins, has recently been described as part of the effect of DHA on the nervous system, since these neuroprotectins act directly as bioactive lipids. According to that, in this work it is presented the LP226, a synthetic hydroxylated fatty acid structurally analogous to DHA, which seeks to restore cerebral lipid homeostasis as a treatment for AD. Results of research After confirming the safety of acute treatment with LP226 in zebrafish and mice, a safe and effective therapeutic dose was established for the chronic treatment of a mice model of AD (5XFAD). The administration of LP226 in 5XFAD mice enabled a proof of concept of the neuroprotective effect of LP226 as reveal by the capacity of LP226 to reverse the spatial memory loss experienced by 5XFAD animals. At a molecular level, treatment with LP226 resulted in an increase in phosphatidylethanolamine species with long chain PUFAs in the brains of 5XFAD mice. These lipid changes were accompanied by a decrease in the production of the C99 fragment and the β-amyloid peptide (Aβ). Changes in the amyloidogenic processing of APP are given by the modulation of β-secretase activity, presumably due to lipid changes in the cerebral membranes. In parallel, treatment with LP226 resulted in a reduction of synaptic loss and neuronal death as well as a restoration of adult neuronal proliferation in the hippocampus in the same animals. Finally, these changes would explain the recovery of spatial memory experienced by 5XFAD animals after treatment with LP226. Conclusion In conclusion, in this work it has been demonstrated the efficacy and safety of LP226, as well as its therapeutic potential in AD. The variety of effects of LP226 treatment on the neuropathological events that occur in AD places it as a good candidate for the treatment of this disease, while suggesting that the hydroxylation of lipid molecules would be a good strategy in the development of drugs for the treatment of neurodegenerative diseases.