In the present work, mice overexpressing mutant amyloid precursor protein (Tg2576), a transgenic model of Alzheimer's disease (AD), are used to investigate a specific lipid profile over the course of disease progression. Using a targeted lipidomic approach, plasma levels of N-acylethanolamines with different length and unsaturation at presymptomatic, mild-symptomatic, and symptomatic disease stages are measured. Moreover, N-acylethanolamines are also assessed in the brain areas most affected in AD. The ethanolamides of palmitic, oleic, arachidonic, eicosapentaenoic, and docosahexaenoic acids do not show any significant alteration in blood of Tg2576 mice at the different stages analyzed, as compared to wild-type. Except for N-docosahexaenoylethanolamine, a general tendency to decrease is instead detected for all measured N-acylethanolamines in the cortex, hippocampus, striatum, and cerebellum of symptomatic Tg2576 mice. Together, the data can help to redefine the range of lipid-associated signals in Alzheimer pathophysiology. Practical Application: The development of novel therapies for AD is strongly narrowed not only by the lack of a full comprehension of underlying pathophysiological mechanisms but also by the absence of affordable, reliable, and noninvasive biomarkers. Hence, there is the practical necessity to acquire accessible blood biomarkers to provide rapid, cost-effective, and critical information to timely identify disease stage and implement preventive strategies aimed at slowing down cognitive decline. In this study, a targeted lipidomics investigation of N-acylethanolamines at different stages of disease progression, clearly indicates that the discovery of innovative blood biomarkers should be refocused on different indices of deranged lipid metabolism for a realistic prediction of the risk of AD. It is investigated that potential alterations of N-acylethanolamines content during disease development in a transgenic mouse model of Alzheimer's disease (AD). Circulating and central N-acylethanolamine levels did not show any alteration in Tg2576 mice at different disease stages.
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