Targeting the kynurenine pathway in Alzheimer's disease

描述(由申请人提供)：阿尔茨海默病(AD)的临床前发展在认知能力下降开始前几十年就开始了。流行病学研究表明，在认知正常的老年人群中，非类固醇抗炎药(NSAIDs)可以抑制环氧合酶(COX-1/COX-2)活性和PGE2的产生，从而阻止AD的发展。鉴于65岁以上人群的阿尔茨海默病患病率每5年翻一番，AD领域的一项根本挑战将是遏制新的AD诊断预计呈指数级增长以及由此造成的重大社会和经济代价。我们最近在野生型和突变型APP小鼠中模拟非类固醇抗炎药的预防效果的研究中，发现了布洛芬对参与色氨酸代谢的酶的表达的抑制作用，这是预防非类固醇抗炎药机制的一个令人信服的线索。TDO2和IDO1酶将必需的氨基酸色氨酸代谢成犬尿氨酸，而犬尿氨酸本身是神经活性分子喹啉酸和犬尿酸的底物；此外，在代谢色氨酸的过程中，合成5-羟色胺的底物TDO2和IDO1将对5-羟色胺水平产生负面影响。重要的是，最近的人体血清生物标记物研究报告显示，AD患者的色氨酸代谢显著增加。因此，在这项提案中，我们将使用遗传学和药理学策略来测试TDO2和IDO1酶是否在AD模型小鼠的早期和晚期AD病理和认知能力下降中起作用。我们还将测试脑脊液和血清中色氨酸代谢物的水平是否与认知测量、A�42/tau比率和/或来自华盛顿大学ADRC的对照组、轻度认知障碍和AD患者的诊断相关。我们拟议的研究将确定色氨酸代谢增加是否与AD的发生有机械联系，以及TDO2/IDO1色氨酸代谢是否可以作为预防和治疗AD的靶点。

DESCRIPTION (provided by applicant): The preclinical development of Alzheimer's disease (AD) begins decades prior to onset of cognitive decline. Epidemiologic studies demonstrate that in cognitively normal aging populations, non-steroidal anti-inflammatory drugs (NSAIDs), which block cyclooxygenase (COX-1/COX-2) activity and PGE2 production, prevent development of AD. Given that the prevalence of AD doubles every 5 years in persons above the age of 65, a fundamental challenge in the AD field will be to stem the projected exponential increase in new AD diagnoses and the significant societal and economic costs that this will cause. A compelling clue to a mechanism underlying NSAID prevention has emerged from our recent studies modeling the preventive effects of NSAIDs in wild type and mutant APP mice, wherein we identified suppressive effects of ibuprofen on expression of enzymes involved in tryptophan metabolism. The enzymes TDO2 and IDO1 metabolize the essential amino acid tryptophan to kynurenine, itself a substrate of the neuroactive molecules quinolinic acid and kynurenic acid; moreover, in metabolizing tryptophan, the substrate for serotonin synthesis, TDO2 and IDO1 will negatively influence levels of serotonin. Importantly, recent biomarker studies in human serum report a significant increase of tryptophan metabolism in AD patients. Thus, in this proposal, we will test whether the enzymes TDO2 and IDO1 contribute to early and late development of AD pathology and cognitive decline using genetic and pharmacologic strategies in AD model mice. We will also test whether levels of tryptophan metabolites in cerebrospinal fluid and serum will correlate with measures of cognition, A�42/tau ratios, and/or diagnosis in control, mild cognitive impairment (MCI), and AD subjects from the ADRC at the University of Washington. Our proposed studies will determine whether increased tryptophan metabolism is mechanistically linked to development of AD and whether TDO2/IDO1 tryptophan metabolism can be targeted in prevention and treatment of AD.