Cortés Malagón Enoc Mariano, López Ornelas Adolfo, Olvera Gómez Irlanda, Bonilla Delgado José
Research Division, Hospital Juárez de México, Mexico City 07760, Mexico.
Genetics Laboratory, Hospital Nacional Homeopático, Mexico City 06800, Mexico.
Brain Sci. 2024 Sep 23;14(9):950. doi: 10.3390/brainsci14090950.
Alzheimer's disease (AD) is the leading cause of dementia, mainly affecting elderly individuals. AD is characterized by β-amyloid plaques, abnormal tau tangles, neuronal loss, and metabolic disruptions. Recent studies have revealed the involvement of the kynurenine (KP) pathway and the aryl hydrocarbon receptor (AhR) in AD development. The KP pathway metabolizes tryptophan to produce neuroactive substances like kynurenine, kynurenic acid, and quinolinic acid. In AD, high levels of kynurenine and the neurotoxic quinolinic acid are associated with increased neuroinflammation and excitotoxicity; conversely, reduced levels of kynurenic acid, which acts as a glutamate receptor antagonist, compromise neuroprotection. Research has indicated elevated KP metabolites and enzymes in the hippocampus of AD patients and other tissues such as blood, cerebrospinal fluid, and urine. However, the finding that KP metabolites are AD biomarkers in blood, cerebrospinal fluid, and urine has been controversial. This controversy, stemming from the lack of consideration of the specific stage of AD, details of the patient's treatment, cognitive deficits, and psychiatric comorbidities, underscores the need for more comprehensive research. AhR, a ligand-activated transcription factor, regulates immune response, oxidative stress, and xenobiotic metabolism. Various ligands, including tryptophan metabolites, can activate it. Some studies suggest that AhR activation contributes to AD, while others propose that it provides neuroprotection. This discrepancy may be explained by the specific ligands that activate AhR, highlighting the complex relationship between the KP pathway, AhR activation, and AD, where the same pathway can produce both neuroprotective and harmful effects.
阿尔茨海默病（AD）是痴呆症的主要病因，主要影响老年人。AD的特征是β-淀粉样蛋白斑块、异常的tau缠结、神经元丢失和代谢紊乱。最近的研究揭示了犬尿氨酸（KP）途径和芳烃受体（AhR）参与AD的发展。KP途径将色氨酸代谢产生神经活性物质，如犬尿氨酸、犬尿喹啉酸和喹啉酸。在AD中，高水平的犬尿氨酸和神经毒性喹啉酸与神经炎症和兴奋性毒性增加有关；相反，作为谷氨酸受体拮抗剂的犬尿喹啉酸水平降低会损害神经保护作用。研究表明，AD患者海马体以及血液、脑脊液和尿液等其他组织中的KP代谢产物和酶水平升高。然而，关于KP代谢产物是否为血液、脑脊液和尿液中的AD生物标志物这一发现一直存在争议。这种争议源于未考虑AD的特定阶段、患者治疗细节、认知缺陷和精神共病，凸显了进行更全面研究的必要性。AhR是一种配体激活的转录因子，可调节免疫反应、氧化应激和外源性物质代谢。包括色氨酸代谢产物在内的各种配体均可激活它。一些研究表明AhR激活会促进AD，而另一些研究则认为它具有神经保护作用。这种差异可能由激活AhR的特定配体来解释，突出了KP途径、AhR激活与AD之间的复杂关系，即同一途径可产生神经保护和有害两种作用。
