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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.
Highlights
Over 55 million people globally live with dementia, but only 25% are properly diagnosed since diagnostic criteria for dementia are unclear [1]
Disease Markers and cerebrospinal fluid (CSF) samples, metabolic profiling has been performed and the results showed that the specific association of amino acids and L-TRP catabolites with Alzheimer’s disease (AD) CSF biomarkers suggests a close relationship with core AD pathology [13]
KYN is the central metabolite of the kynurenine pathway (KP) and is catabolized to anthranilic acid (AA), 3-hydroxy-Lkynurenine (3-HK), and kynurenic acid (KYNA) by kynureninase (KYNU), kynurenine 3-monooxygenase (KMO), and kynurenine aminotransferase I-IV (KAT I-IV), respectively [81,82,83]. 3-HK is converted to 3-hydroxyanthranilic acid (3-HANA), the precursor to the neurotoxic metabolite, quinolinic acid (QA) [84, 85], and xanthurenic acid (XA) [86] by KYNU and KAT I-IV, respectively. 3-Hydroxyanthranillate-3,4-dixogygenase (3-HAAO) catalyzes the conversion of 3-HANA to QA [87, 88]
Summary
Over 55 million people globally live with dementia, but only 25% are properly diagnosed since diagnostic criteria for dementia are unclear [1]. Disease Markers and cerebrospinal fluid (CSF) samples, metabolic profiling has been performed and the results showed that the specific association of amino acids and L-TRP catabolites with AD CSF biomarkers suggests a close relationship with core AD pathology [13]. Another metabolomic analysis of AD patients and healthy seniors suggests that the involvement of polyamine and L-TRP-KYN metabolisms was observed in the postmortem cerebrospinal fluid (PCSF) samples [14]. We discuss the applicability of KP metabolites as biomarkers for AD and provide references for the search for biomarkers and therapeutic targets
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