The potential role of kynurenines in Alzheimer’s disease: pathomechanism and therapeutic possibilities by influencing the glutamate receptors

Abstract

The pathomechanism of neurodegenerative disorders still poses a challenge to neuroscientists, and continuous research is under way with the aim of attaining an understanding of the exact background of these devastating diseases. The pathomechanism of Alzheimer's disease (AD) is associated with characteristic neuropathological features such as extracellular amyloid-β and intracellular tau deposition. Glutamate excitotoxicity and neuroinflammation are also factors that are known to contribute to the neurodegenerative process, but a cerebrovascular dysfunction has recently also been implicated in AD. Current therapeutic tools offer moderate symptomatic treatment, but fail to reduce disease progression. The kynurenine pathway (KP) has been implicated in the development of neurodegenerative processes, and alterations in the KP have been demonstrated in both acute and chronic neurological disorders. Kynurenines have been suggested to be involved in the regulation of neurotransmission and in immunological processes. Targeting the KP, therefore, offers a valuable strategic option for the attenuation of glutamatergic excitotoxicity, and for neuroprotection.

Trisomy 21 activates the kynurenine pathway via increased dosage of interferon receptors

“…Interestingly, the KP has been consistently implicated in AD progression. Multiple studies have reported elevated levels of metabolites in the KP in people with AD, and, in many of these studies, KP dysregulation has been positively correlated with AD progression (reviewed in 54 ). Furthermore, IDO1 inhibition reversed AD pathology in a mouse model of AD 55 .…”

Association of amine biomarkers with incident dementia and Alzheimer's disease in the Framingham Study

“…[38] The KP can be activated in response to various pro-inflammatory factors, including Aβ1–42, [39] and this process has been observed in the brain of AD patients at the level of amyloid plaques. [40] Inflammation is now considered an important and early event in AD pathophysiology.…”

“…In the long run, metabolites from the KP, especially quinolinic acid, could participate to neurodegeneration through glutamate excitotoxicity. [38] Inhibition of key enzymes of the KP resulted in amelioration of neurodegeneration in mice and fly models of AD. [42,43] Thus, metabolites from the KP could provide a range of promising therapeutic targets.…”

Exploring the Etiological Links behind Neurodegenerative Diseases: Inflammatory Cytokines and Bioactive Kynurenines

“…The pro-inflammatory cytokine IFN-γ activates IDO, formamidase, and KMO activities in human microglial cells and macrophages, resulting in increased QA synthesis. QA concentrations in the brain were reduced by anti-inflammatory steroid agent dexamethasone after immune stimulation [114].…”