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发作前数十年就开始了。流行病学研究表明，在认知功能正常的老年人群中，非甾体抗炎药（NSAID）可阻断环氧合酶（考克斯-1/考克斯-2）活性和PGE 2的产生，从而预防AD的发生。鉴于AD的患病率在65岁以上的人群中每5年翻一番，AD领域的根本挑战将是阻止新AD诊断的预计指数增长以及这将导致的重大社会和经济成本。NSAID预防的潜在机制的一个令人信服的线索已经出现在我们最近的研究中，这些研究模拟了NSAID在野生型和突变型APP小鼠中的预防作用，其中我们鉴定了布洛芬对参与色氨酸代谢的酶的表达的抑制作用。酶TDO 2和IDO 1将必需氨基酸色氨酸代谢为犬尿氨酸，犬尿氨酸本身是神经活性分子喹啉酸和犬尿氨酸的底物;此外，在代谢色氨酸时，5-羟色胺合成的底物，TDO 2和IDO 1将对5-羟色胺的水平产生负面影响。重要的是，最近对人类血清的生物标志物研究报告AD患者的色氨酸代谢显着增加。因此，在本提案中，我们将使用遗传和药理学策略在AD模型小鼠中测试酶TDO 2和IDO 1是否有助于AD病理学和认知衰退的早期和晚期发展。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 β 42/tau比率和/或来自华盛顿大学ADRC的对照、轻度认知障碍（MCI）和AD受试者的诊断相关。我们提出的研究将确定色氨酸代谢的增加是否与AD的发展有机械联系，以及TDO 2/IDO 1色氨酸代谢是否可以作为预防和治疗AD的目标。

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, Aß42/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.