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开始。流行病学研究表明，在认知正常的老年人群中，非甾体抗炎药（NSAIDs）可以阻断环氧化酶（COX-1/COX-2）活性和PGE2的产生，从而预防AD的发生。鉴于65岁以上人群中阿尔茨海默病的患病率每5年翻一番，阿尔茨海默病领域的一个根本挑战将是遏制预计的阿尔茨海默病新诊断的指数增长以及由此造成的重大社会和经济成本。我们最近在野生型和突变型APP小鼠中模拟了非甾体抗炎药的预防作用，发现了布洛芬对色氨酸代谢相关酶表达的抑制作用，这为非甾体抗炎药预防机制提供了令人信服的线索。酶TDO2和IDO1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酸的底物；此外，在色氨酸代谢过程中，血清素合成底物TDO2和IDO1会对血清素水平产生负面影响。重要的是，最近的人类血清生物标志物研究报告了AD患者色氨酸代谢的显著增加。因此，在本研究中，我们将在AD模型小鼠中采用遗传和药理学策略测试TDO2和IDO1酶是否参与AD病理的早期和晚期发展以及认知能力下降。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、A - 42/tau比值、对照组、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增加是否与AD的发展有机制联系，以及TDO2/IDO1色氨酸代谢是否可以靶向预防和治疗AD。

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.