The lipid amidase NAAA as a therapeutic target for Alzheimer's disease

项目总结

PROJECT SUMMARY Current therapies do not alter the course of Alzheimer's disease (AD), a devastating neurodegenerative illness that affects 5.8 million people in the United States and 44 million people worldwide. Thus, an urgent goal for research is to identify points of control for neurodegeneration, which may be targeted to slow down AD progression. In this application, we propose to test the hypothesis that the enzyme N-Acylethanolamine Acid Amidase (NAAA) is one such focal point. NAAA is a lysosomal lipid hydrolase that converts palmitoylethanolamide (PEA) into palmitate. PEA is an endogenous agonist of the neuroprotective nuclear receptor PPAR-α, whereas palmitate promotes neurodegeneration by suppressing the transcription co- activator PGC1α, a key regulator of neuronal energy metabolism and survival. Preliminary experiments have shown that NAAA transcription is abnormally elevated in persons with sporadic AD and in various animal models of neurodegeneration, including the 5xfAD model of AD. In the same models, we found that pharmacological NAAA inhibition and/or genetic NAAA deletion exert marked protective effects. Based on these results, we hypothesize that dysfunctions in NAAA-regulated lipid signaling may be critically involved in the pathogenesis of AD. We have three specific aims. Aim 1. Characterize NAAA-regulated lipid signaling in mouse models of AD. Using 5xfAD and Tau P301S mice, two mouse lines that capture distinct aspects of AD pathology, we will identify age-dependent, regionally selective changes in NAAA- regulated lipid signaling, which might precede and/or accompany neurodegenerative alterations and cognitive impairment. Aim 2. Determine the impact of pharmacological NAAA inhibition in mouse models of AD. We will assess the impact of chronic administration of the compounds ARN19702 and ARN16186 – two brain-permeant NAAA inhibitors discovered by our team – on molecular, morphological and behavioral markers of disease progression in 5xfAD and Tau P301S mice. Aim 3. Determine the impact of genetic NAAA deletion in mouse models of AD. Using our conditional NAAA-/- mice, we will generate NAAA- deficient 5xfAD and Tau P301S mice to evaluate the impact of NAAA deletion on disease progression. In Aims 2 and 3, we will also explore molecular and cellular substrates for the effects of NAAA inhibition/deletion using single-cell RNA sequencing. The proposed studies will elucidate the functional roles of NAAA-regulated lipid signaling in the pathogenesis of AD and, if our hypothesis is verified, will validate NAAA as a novel molecular target for the treatment of this disorder.