Kynurenine Pathway Metabolites as Biomarkers in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that deteriorates cognitive function. Patients with AD generally exhibit neuroinflammation, elevated beta-amyloid (Aβ), tau phosphorylation (p-tau), and other pathological changes in the brain. The kynurenine pathway (KP) and several of its metabolites, especially quinolinic acid (QA), are considered to be involved in the neuropathogenesis of AD. The important metabolites and key enzymes show significant importance in neuroinflammation and AD. Meanwhile, the discovery of changed levels of KP metabolites in patients with AD suggests that KP metabolites may have a prominent role in the pathogenesis of AD. Further, some KP metabolites exhibit other effects on the brain, such as oxidative stress regulation and neurotoxicity. Both analogs of the neuroprotective and antineuroinflammation metabolites and small molecule enzyme inhibitors preventing the formation of neurotoxic and neuroinflammation compounds may have potential therapeutic significance. This review focused on the KP metabolites through the relationship of neuroinflammation in AD, significant KP metabolites, and associated molecular mechanisms as well as the utility of these metabolites as biomarkers and therapeutic targets for AD. The objective is to provide references to find biomarkers and therapeutic targets for patients with AD.

Mechanistic Insight into Diosmin-Induced Neuroprotection and Memory Improvement in Intracerebroventricular-Quinolinic Acid Rat Model: Resurrection of Mitochondrial Functions and Antioxidants

“…The findings of this study indicated an increase in oxidonitrosative stress and depreciation of endogenous antioxidant levels by QA-ICV in the mitochondrial fraction of the whole-brain homogenate. Previous studies also indicate NMDAR-dependent and NMDAR-independent increase in free radicals and inflammatory deterioration by QA in experimental animals [ 5 , 9 , 10 ]. In current experiments, QA enhanced lipid peroxidation and total nitrites in the brain.…”

“…QA (2,3-pyridine dicarboxylic acid) is an excitotoxin similar to glutamate and is capable of evoking neurodegeneration as its concentration amplifies with age [ 5 ]. The antagonists of NMDARs and amino phosphonates can prohibit the neurodegenerative excitotoxicity of QA, which suggests that QA acts through NMDARs in the brain [ 9 ]. BBB acts as a protective barrier and limits the neurotoxicity of QA.…”

“…The activity of QPRT is maximum in the olfactory bulb and lowermost in the cortex, hippocampus, and striatum, where QA may exert neurotoxic action to a great extent in these brain regions. These brain areas are adversely affected in numerous neurodegenerative disorders, such as AD, PD, HD, and schizophrenia that lead to severe cognitive decline [ 9 , 10 ]. In this study, QA was administered directly through the ICV route to overcome the BBB constraint in the adult rats.…”

“…e antagonists of NMDARs and amino phosphonates can prohibit the neurodegenerative excitotoxicity of QA, which suggests that QA acts through NMDARs in the brain [9]. BBB acts as a protective barrier and limits the neurotoxicity of QA.…”

“…QA is a metabolic inhibitor that makes it a potent neurotoxin [ 8 ]. QA inhibits monoamine oxidase-B (MAO-B), gluconeogenesis ( via phosphoenolpyruvate carboxykinase), creatine kinase, mitochondrial complexes, cellular respiration, and decreases ATP levels [ 9 ]. QA can augment oxidative stress and decline antioxidants in an NMDAR-dependent or -independent manner.…”