Research progress of kynurenine pathway in Alzheimer's disease

Wei Lv, Yan-Qing Han, Xiao-Yu Guo, Rong-Jie Wang, Zhi-Rong Wang

1. Department of Neurology, Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi, China 2. Shanxi Cardiovascular Hospital, Shanxi Medical University, Taiyuan 030000, Shanxi, China

Keywords:Kynurenine pathway Alzheimer's disease Vascular dementia Kynurenine Quinolinic acid

ABSTRACT The kynurenine pathway (KP) has been shown to be involved in the pathophysiology of dementia diseases. Among the dementia diseases, the neurodegenerative diseases Alzheimer's disease and cerebrovascular diseases are vascular. The highest incidence of dementia. KP activation results in the production of neuroactive metabolites, which may interfere with normal neuronal function, leading to the appearance of symptoms of cognitive impairment. This review investigated KP's involvement in the neurological diseases Alzheimer's disease and vascular dementia, suggesting that KP is a potential therapeutic target for both diseases.

Dementia is the fourth killer that threatens human life. One new case of dementia occurs every 3 seconds. The global economic burden caused by dementia is as high as US $ 1 trillion per year. Chronic progressive neurodegenerative disease Alzheimer's disease is the most common type of dementia in old age, and it is also one of the most common chronic diseases in old age, accounting for about 50% to 70% of dementia in old age. Alzheimer's disease (AD) is a degenerative disease of the central nervous system that is characterized by progressive cognitive dysfunction and behavioral impairment in the elderly and preseniles [1]. Clinical manifestations include memory impairment, aphasia, apraxia, loss of recognition, impaired visual spatial ability, impairment of abstract thinking and computing power, personality and behavior changes, etc. As the population ages, it shows an increasing prevalence, which has attracted recent research interest. Although the mechanism of AD has been extensively studied, the exact molecular basis remains to be clarified [2]. Studies have found that (kynurenine pathway, KP) metabolites are closely related to AD. This review focuses on the mechanism of KP in AD. The regulatory role of KP in potential treatment strategies for the disease is also described.

1.Kynurenine pathway

KP is the major pathway for tryptophan (TRP) metabolism in most mammalian tissues (Figure 1) [1, 2]. This pathway accounts for about 95% of systemic TRP metabolism and involves several diseases of the peripheral and central nervous system, including cancer, inflammatory diseases, neurological diseases, and mental illness [3]. In mammals, the degradation of TRP is controlled by one of the two rate-limiting enzymes indoleamine-2,3-dioxygenase (IDO1 and IDO2) or tryptophan 2,3-dioxygenase (TDO2) [1], these enzymes catalyze TRP to produce N-formyl kynurenine under the regulation of cytokines, steroids and growth factors (see Figure 1) [4]. Next is the synthesis of the first stable molecule of this pathway, kynurenine (l-KYN). The subsequent metabolism of I-KYN passes one of three mechanisms: (1) Deamination of I-KYN by the kynurenine aminotransferase (KAT) family, leading to the production of kynurenic acid (KYNA) [5]; 2) The degradation of l-KYN by kynureninase leads to the production of anthranilic acid; or (3) the hydroxylation of l-KYN by kynurenine monooxygenase (KMO) produces 3-hydroxykynurenine (3-HK); 3-HK is subsequently converted to 3-hydroxyanthranilic acid (3-HANA) by kynurenase (KYNU), and then 3,4-dioxygenated by 3-hydroxyanthranilic acid The enzyme (3-HAO) is oxidized to 2-amino-3-carboxymuconate 6-semialdehyde (ACMS). Under physiological conditions, this intermediate spontaneously recombinates to form quinolinic acid (QUIN), which is subsequently transaminated by quinolinate phosphate ribosyltransferase (QPRT) to form nicotinic acid, eventually forming NAD + [6].

2.Kinesine pathway metabolites

2.1KYNA

KYNA is a tryptophan metabolite produced by kynurenine aminotransferase (KAT) aminotransfer of kynurenine, and is mainly synthesized in glial cells [7]. Kessler and colleagues first discovered that this intermediate blocks the glycine (Gly) binding site of the NMDA receptor at low concentrations [8]. Blocking the glutamate-binding site of the NMDA receptor complex requires a 10-20-fold higher concentration than the Gly-binding site, while KYNA treats amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), alginate receptors show weak antagonism [9]. It is also a non-competitive inhibitor of 7-nicotinic acetylcholine receptors, most of which are located at the presynaptic terminal, and are the main target of endogenous KYNA in the brain [10, 11]. At high molar concentrations, KYNA is a non-selective antagonist of the NMDA receptor. Through this regulation of glutamate signaling and antioxidant activity, KYNA can offset the neurotoxicity transmitted by QUIN, 3-HK, and 3-HANA. Potential antioxidant properties, although such high local concentrations are rarely achieved under physiological or pathological conditions. Various electrophysiological and behavioral experiments have shown that a slight increase in brain KYNA concentration can also reduce excitatory transmission in the brain [12]. It is shown that KYNA is an effective free radical scavenger and antioxidant. These characteristics suggest that KYNA as a putative neuroprotective agent can offset the excitotoxicity of glutamate at multiple sites. KYNA plays an important role in the regulation of neural plasticity and cognitive function [13]. Therefore, under normal physiological conditions, the metabolic quantities on both sides of l-KYN metabolism must be strictly adjusted to ensure that the proportion of these metabolites is maintained at a level that prevents cytotoxicity. Accumulation of KYNA content in rat brain during aging has been reported. There are several neurodegenerative diseases, such as AD, amyotrophic lateral sclerosis, migraine and epilepsy, the pathogenesis of which is thought to involve reducing brain KYNA levels, and high levels of this compound have been found in schizophrenia Patient's brain [14, 15].

2.2 3-Hk and 3-HANA

The neuroactive KP metabolite 3-HK is synthesized by KMO and generates free radicals through oxidative interactions [16]. In fact, 3-HK treatment of cultured striatum and cortical neurons will reduce vitality. Co-injection of 3-HK and QUIN in the striatum can enhance excitotoxic neuron disease [9]. Further down the pathway, 3-HANA is synthesized, and the metabolite 3-HANA is prone to auto-oxidation and thus produces highly reactive substances, such as hydrogen peroxide and hydroxyl radicals, which are enhanced by SOD but eliminated by catalase. These data indicate that 3-HK and 3-HANA-mediated neurotoxicity is caused by ROS and can be offset by catalase activity [15]. However, it has also been reported that both 3-HK and 3-HANA also have antioxidant activity [17].

2.3 QUIN

QUIN is a weaker, competitive agonist that selectively activates N-methyl-d-aspartate (NMDA) receptors [16]. QUIN can directly interact with free iron ions to form toxic complexes, exacerbating reactive oxygen species, oxidative stress, and excitotoxicity [9]. It was identified as a potential neurotoxin when the first intraventricular injection in mice caused strong seizures. Subsequent research found that injection of QUIN into the striatum of the rodent brain has excitatory toxicity, causing dose-dependent axon retention damage near the injection site, which can be rescued by co-administration of selective NMDA receptor antagonists. QUIN levels are slightly higher than physiological levels and are also sufficient to cause rapid neural damage in rat cortical cortical cell cultures [18]. High levels of quinoline can cause excitotoxic cell death. The hippocampus and striatum are the brain regions most sensitive to QUIN neurotoxicity and are also toxic to oligodendrocytes. The highly efficient properties of QUIN may be due to the mechanism through which this neurotoxin can cause neuronal damage. QUIN not only stimulates the neuron release of glutamate, but also inhibits the astrocyte reuptake of the neurotransmitter, and reduces the activity of glutamine synthetase, which promotes the production of glutamine by glutamate and ammonia [ 19, 20]. Sustained activation of high concentrations of extracellular glutamate and excitatory neurons can cause excitotoxicity due to increased penetration of Ca 2+ through the ion channel complex leading to mitochondrial dysfunction, cytochrome C release, protease activation, and NOS Activation, a series of reactions lead to necrosis of neurons [10]. Quinolinic acid can also induce local inflammation of the nervous system, increase the expression and release of chemical chemokines, such as monocyte chemotactic protein-1 (MCP-1) and RANTES, and promote neurons and astrocytes Apoptosis [21].

3.Kinesine pathway and Alzheimer's disease

Changes in KP have been found in some neurological and more specific neurodegenerative diseases, such as Huntington's disease, Parkinson's disease, multiple sclerosis, focal dystonia, and migraine[22]. Increasing evidence suggests that the KYN pathway is involved in the pathogenesis of AD. The pathogenesis of AD is not fully understood. Its typical neuropathological features are extracellular deposition of amyloid beta (Aβ) and intracellular deposition of tau protein [23]. Cerebrovascular hypoperfusion promotes Aβ deposition, and secondary hypoxic cerebral neurons become the pathological basis of neuroinflammation and neurotoxicity [24]. Aβoligomerization is thought to trigger a series of events, including oxidative stress, glutamate excitotoxicity and inflammation, which have been found to be associated with KP.

Initially, there was a large increase in reactive microglia in the brains of AD patients, most of them located around dense plaques containing Aβ. Aβinduces microglial phenotype activation and regulates acute and chronic expression of pro-inflammatory genes, leading to activation of the complement system and release of cytokines, chemokines, and acute-phase proteins, which may produce potentially toxic substances. Interestingly, in addition to many pro-inflammatory genes, the expression of enzymes in KP is also significantly activated by Aβ[25]. Microarray analysis of Aβstimulated microglia gene expression profiles showed that IDO production increased by an average of more than 40 times at 24 hours (278 times by real-time PCR), and still increased significantly at 96 hours. Similarly, the expression of kynurenase increased 3.6-fold, while the expression of KAT II did not increase. These data indicate that there is no simple relationship between QUINA and dementia in AD compared to the putative neuroprotective agent KYNA, even though Aβ in the brain is characteristic of AD and its association with KP has been noted. IDO and QUINA concentrations increased in amyloid plaques and microfibrillary tangles, and Aβ induced IDO and kynurenase activity. The stimulation of Aβ on microglia changes to the direction of KYN pathway to produce neurotoxic QUINA. As the levels of 3-HK and 3-HANA in the brain and serum increase, the substance can mediate oxidative stress and cause damage to neural tissue Afterwards, the mechanism of Aβ accumulation, glial activation and KP upregulation will further aggravate neurodegenerative diseases [26]. In a recent study by Guillemin et al., IDO and QUINA were indeed overproduced in human AD hippocampal macrophages and microglia. QUINA is a direct activator of the NMDA receptor, increasing basal L-glutamic acid release in a NMDA receptor-mediated manner. Continuous local depolarization and cation influx cause further release of L-glutamic acid. This vicious cycle triggered intracellular events, mainly due to the swelling of neurons due to the increase in cation concentration and the subsequent inflow of water, followed by the necrosis of neurons due to the degradation of calcium-dependent neurons [27]. QUINA production also promotes glial cell activation and cytokine release, while pro-inflammatory cytokines enhance Aβ activation of IDO, establishing a harmful positive feedback cycle [28]. Intervention at these critical steps may be a target for potential treatments.

Baran first found that KP changes were observed in patients with pathologically confirmed AD. KYNA levels were significantly increased in the caudate nucleus and putamen, which was associated with increased KAT I activity. The level of aspartate aminotransferase in cerebrospinal fluid of AD patients was elevated, and the mitochondrial form of this enzyme was identified as KAT IV. KYNA levels in serum and erythrocytes of AD patients decreased, but there was no significant change in KAT I, II activity. In AD patients, the serum concentrations of TRP and KYNA decreased, and the content of kynurenine and 3-hydroxykynurenine increased, while the increased degradation of TRP and the simultaneous changes in kynurenine levels increased the KYN / TRP ratio, suggesting KP The activity of the first key enzyme IDO is enhanced, and the TRP / KYN ratio has also been shown to correlate with the level of cognitive impairment in patients, which proves that peripheral KP is activated in AD. In contrast, KYNA concentrations in the striatum of the brain of post-mortem patients with AD have increased, which is considered to be a compensation mechanism for excessive activation of the striatum-frontal ring caused by neuronal loss in the cortical region [29] . It was found that a part of senile plaques formed by the accumulation of Aβ outside nerve cells in AD. These plaques have a higher content of microglia and reactive astrocytes, and showed IDO and QUINA immunoreactivity. Aβ induced human giant Significant increases in phage and microglia IDO expression and QUINA. Since KYNA and QUIN in KP have diametrically opposite effects, changes in these two major KYN metabolites appear to be related to cognitive impairment in AD patients [11].

Aβ1-42 in Aβ has been reported to increase the production of quinolinic acid to the neurotoxic concentrations of human macrophages and microglia, which may contribute to the oxidation process of AD [30]. Similarly, Aβ1-42-induced increase in IDO expression, allowing 3-hydroxykynurenine and 3-hydroxyanthranilic acid-induced oxidative stress, may contribute to neurodegeneration, but Aβ1-40 has no similar effect. A recent study suggests that TDO-mediated KP activation may be important in nerve fiber formation [28]. TDO is an isozyme of IDO in KP. More and more studies have shown that TDO-mediated KP metabolism is involved in the development of tumors, neuropsychiatric diseases, and inflammation-related diseases [31]. The role in KP has been proposed. A recent study suggests that TDO-mediated KP activation may be important in nerve fiber formation. Studies have shown that TDO is highly expressed in the brains of AD patients and in 3xTg mouse models of AD. In addition, TDO co-localizes with QUINA, neurofibrillary tangles, and amyloid deposition in the hippocampus of AD patients after death. Foreign studies using TDO inhibitors can significantly improve the climbing performance of AD fruit flies [32]. It has been suggested that in this case, TDO activation is driven by lactase and cortisol (Wu et al., 2013). Regarding potential therapeutic targets, KYNA has positive significance for AD treatment, and blocking KP can have a protective effect on a mouse model of Alzheimer's disease [33]. By increasing enkephalinase gene expression and enzyme activity, Aβ degradation is promoted. Probenecid can increase KYNA content in the brain, prevent soluble Aβ from damaging neurons, and partially restore memory in patients with AD [24]. The small molecule KMO inhibitor JM6 has been shown to reduce the extracellular glutamate concentration and increase the KYNA concentration in rat brain and serum after oral administration, which can improve spatial learning and memory ability, anxiety-like performance and synaptic loss in mice However, it did not affect the accumulation of Aβ[21]. IDO inhibitors, as drugs with new drug targets and new mechanisms, have been used to treat tumors, depression, AD, cataracts and many other diseases. Other studies have shown that IDO inhibitor berberine can improve cognitive dysfunction in AD mouse models [34]. These findings seem to provide new therapeutic opportunities, and the development of new compounds offers broad prospects for brain neuroprotection [35].

4. Conclusion and outlook

There is more and more evidence that KP metabolites are closely related to the pathology of AD, and KP may be an effective treatment for AD. Recent findings suggest that targeted inhibition of this pathway by inhibiting the KP rate-limiting enzymes IDO, TDO, or KMO has proven to be an effective neuroprotective strategy for these diseases [20], and the specific mechanism remains to be studied Explore.