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ABERRANT METABOLISM OF NEUROVASCULAR UNIT CELLS IN PARKINSON'S DISEASE
N.A. Kolotyeva , A.K. Berdnikov, N.A. Rozanova, A.V. Zubova, A.S. Averchuk Research Center of Neurology, 80 Volokolamskoye Highway, Moscow, 125367, Russia. * Corresponding author: [email protected]
Abstract. The focus of this review is on the study of aberrant metabolism in brain cells in Parkinson's disease. Parkinson's disease is the second most prevalent neurodegenerative disorder, characterized by the aggregation of the pathological protein a-synuclein, loss of dopaminergic neurons in the compact part of the substantia nigra, leading to a combination of motor and non-motor symptoms. While the hallmark motor symptoms of PD are well-documented, emerging research sheds light on intricate metabolic changes occurring at the cellular level, providing new insights into the path-ophysiology of the disease. Studying the role of endogenous small molecules in protein-metabolite intermolecular interactions, conformational rearrangements of protein molecules, especially membrane receptors and transporters in regulating blood-brain barrier permeability, modulation of signaling transduction processes in neuroinflammation and neurodegeneration, remains pertinent.
Keywords: aberrant metabolism, Parkinson's disease, small molecules, NVU cells.
List of Abbreviations
6-OHDA - 6-hydroxydopamine AQP4 - aquaporin 4 BBB - blood-brain barrier CD - cluster of differentiation CNS - central nervous system DAMPs - damage-associated molecular patterns
GLUT-1 - glucose transporter type 1 GPR81 - G protein-coupled receptor 81 HMGB1 - high-mobility group box 1 protein
IL - interleukin LDH - lactate dehydrogenase LPS - lipopolysaccharide MCT - monocarboxylate transporter MIF - macrophage migration inhibitory factor
MPTP - 1 -methyl-4-phenyl- 1,2,3,6-tetrahy-dropyridine
mtDNA - mitochondrial DNA NAD+ - nicotinamide adenine dinucleotide NF-kB - Nuclear factor kappa B NLRP3 - NOD-, LRR- and pyrin domain-containing protein 3
NVU - neurovascular unit OXPHOS - oxidative phosphorylation PD - Parkinson's disease PINK1 - PTEN induced kinase 1 PRKN - Parkin protein
ROS - reactive oxygen species
TLR - tall-like receptor
TNF-a - tumor necrosis factor alpha
Introduction
Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, characterized by the aggregation of the pathological protein a-synuclein, loss of dopaminergic neurons in the compact part of the substantia nigra, leading to a combination of motor and non-motor symptoms. Clinically, the disease is characterized by the classical symptoms consisting of rigidity, tremor, and bradykinesia (Clarke, 2007). The prevalence of this chronic disease is increasing faster than Alzheimer's disease; the incidence rate doubled between 1990 and 2015 and is projected by some researchers to double again by 2040, causing alarming medical and economic concerns (Dorsey & Bloem, 2018).
The neurovascular unit (NVU) is a complex dynamic multi-cellular structure consisting of neurons, glial cells (astrocytes, oligodendro-cytes, microglia), vascular cells (endothelial cells, pericytes, smooth muscle cells), that demonstrates the connection between brain cells and the microcirculatory network. The proper functioning of the NVU provides maintenance of the homeostatic microenvironment of the brain, through control of the blood-
brain barrier (BBB) and cerebral blood flow. Impaired functioning of the NVU contributes to neurovascular pathology, neuroinflammation, and causes the development of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and others (Chen et al., 2022; Salmina et al., 2015; Sonninen et al., 2020).
Studying the mechanisms of PD development, the role of endogenous small molecules in protein-metabolite intermolecular interactions, conformational rearrangements of protein molecules, especially membrane receptors and transporters in regulating BBB permeability, modulation of signaling transduction processes in neuroinflammation and neurodegeneration, remains pertinent. While the hallmark motor symptoms of PD are well-documented, emerging research sheds light on intricate metabolic changes occurring at the cellular level, providing new insights into the pathophysiology of the disease (Blaszczyk, 2020; Lehtonen et al., 2019; Murali Mahadevan et al., 2021; Sonninen et al., 2020). Currently, there is a point of view that PD cannot be explained only in terms of oxidative stress or energy deficiency; PD has been shown to be a complex metabolic disorder (Anandhan et al., 2017).
Metabolic dysfunction in PD
Metabolic dysfunction in PD involves disruptions in various cellular processes, including energy production, mitochondrial function, and protein homeostasis. In their study, Shao et al. showed that PD leads to changes in metabolism, reflected in the concentrations of several substances in human blood plasma (Shao et al., 2021). Specifically, significant decreases were observed in the concentrations of free fatty acids, steroid hormones, and caffeine metabolites, along with an increase in the concentration of bile acids and bacterial metabolites. Changes in lipid metabolism have been observed in PD, with alterations in lipid composition in cell membranes and disruptions in lipid homeostasis (Alecu & Bennett, 2019; Jin et al., 2019). These changes may influence cellular signalling pathways and contribute to neurodegeneration (Shao et al., 2021).
Emerging evidence suggests that alterations in glucose metabolism may play a crucial role in PD pathogenesis (Hong et al., 2020; Sánchez-Gómez et al., 2021). Impaired glucose utilisation and insulin resistance have been observed in the brains of PD patients (Cai et al., 2019; Sergi et al., 2019), linking metabolic disturbances to neuroinflammation and neuronal death. Understanding these metabolic changes opens avenues for potential therapeutic interventions targeting cellular energy regulation and metabolic pathways (Cai et al., 2019; Kri-korian et al., 2019).
Mitochondria, the cellular powerhouses responsible for energy production, are significantly affected in PD. Dysfunction in the electron transport chain and impaired oxidative phosphorylation lead to imbalanced in the NAD+/NADH ratio, decreased ATP production. Alterations in the mitophagy mechanism lead to cessation of normal mitochondrial recycling (J. Liu et al., 2019; Malpartida et al., 2021). Additionally, dysfunctional mitochondria contribute to the generation of reactive oxygen species (ROS), causing oxidative stress and damaging cellular components (Chang & Chen, 2020; C. Chen et al., 2019; Park et al., 2018). Mitochondrial dysfunction, a key player in PD pathology (Grünewald et al., 2019; Henrich et al., 2023), leads to impaired oxidative phosphorylation (Bose & Beal, 2019; Milanese et al., 2019; Shen et al., 2020) and increased production of ROS, contributing to cellular stress and damage. Additionally, dysregulation of autophagy, the cellular recycling system (Fe-dotova et al., 2022; Haque et al., 2022; Tu et al., 2021), further exacerbates protein aggregation and the formation of Lewy bodies, pathological hallmarks of PD.
There is increasing research showing the contribution of inflammation to PD. Parkin protein (PRKN) and PTEN induced kinase 1 (PINK1) deficiency have been shown to result in the release of mitochondrial DNA (mtDNA), mitophagy, causing inflammation. Increased levels of IL6, circulating cell-free mtDNA, are considered indicators of PD progression due to PRKN/PINK1 mutations (Borsche et al., 2020). On the other hand, it has been shown that Parkin inhibits the
release of damaged mitochondrial proteins into the extracellular space, promoting their degradation in lysosomes (Todkar et al., 2021).
Furthermore, the gut-brain axis is gaining attention as a potential contributor to PD pathology (Cirstea et al., 2020; Klann et al., 2022). Microbiota alterations and intestinal inflammation may influence the progression of PD (C.-H. Lin et al., 2019) , highlighting the intricate interplay between the gastrointestinal system and the central nervous system. Targeting the gut microbiome could offer novel strategies for managing metabolic dysfunction in PD and potentially modifying disease progression (Hu et al., 2024).
Understanding these metabolic changes summarized in Figure 1 and is crucial for developing targeted therapeutic strategies aimed at preserving cellular function and slowing the progression of Parkinson's disease. Researchers and clinicians are exploring various avenues to intervene in these metabolic pathways in the cells of the neurovascular unit of the brain, offering potential avenues for disease modification and improved management of PD.
Metabolism of brain cells in PD
In the context of PD, there is growing recognition of the involvement of astrocytes in the disease process, and understanding the metabolic changes within these cells is of significant interest. Similar to neurons, astrocytes rely heavily on mitochondrial function for energy production. Mitochondrial dysfunction in astro-cytes, characterized by impaired oxidative phosphorylation and increased production of ROS, has been observed in PD (Ramos-Gonzalez et al., 2021). This dysfunction contributes to cellular stress and may influence the overall metabolic environment in the brain. It has been established that individuals with Parkinson's disease exhibit reduced expression of proteins associated with oxidative phosphorylation (OXPHOS) in mitochondria (Chen et al., 2022). Astrocytic asthenia in PD may contribute to neuronal death through decreased home-ostatic support, increased oxidative stress and failed neuroprotection (Ramos-Gonzalez et al., 2021).
There is also a connection between a-synuclein pathology and mitochondrial functions. a-synuclein, taken up by astrocytes, exerts a detrimental effect on mitochondria, causing its fragmentation, damaging mitochondrial membranes, and mtDNA. It was revealed that TNF-a and a-synuclein fibrils compete to control the immune reactive response of astrocytes in PD. Astrocytes secrete proinflammatory cy-tokines, which leads to impaired mitochondrial respiration (Russ et al., 2021). In their study, Lindström et al. demonstrate that astrocytes are capable of phagocytosing and partially utilizing alpha-synuclein oligomers through the lysoso-mal pathway. It has also been shown that the internalization of a-synuclein leads to mito-chondrial dysfunction within astrocytes (Lindström et al., 2017). Furthermore, crosstalk between astrocytes and microglia has been shown to result in increased degradation of a-synuclein, which involves the transfer of protein aggregates from astrocytes to microglia, which may be an important mechanism for the clearance of protein aggregates within affected brain (Rostami et al., 2021).
Astrocytes are essential for glucose metabolism and energy support in the brain. In PD, there is evidence of disrupted glucose metabolism in astrocytes, potentially contributing to energy deficits in the affected brain regions. There is also evidence indicating a decrease in the expression of pyruvate dehydrogenase ki-nase, a regulatory protein of pyruvate dehydro-genase, as well as an increase in aconitase activity within the first 7 days after in vivo modelling in rats using the 6-hydroxydopamine (6-OHDA) and fluorocitrate-induced neuroinflammation of Parkinson's disease type (K. Kuter et al., 2019). Moreover, a decrease in the amount of glycogen in glial cells was observed both at 7 and 28 days after exposure in the same models. Impaired glucose uptake and utilization by astrocytes may compromise their ability to provide energy substrates to neighbouring neurons (Sonninen et al., 2020). Changes in lactate metabolism may impact the energy supply to neurons, influencing their function and survival. In their study, Kuter et al. demonstrated that the lactate concentration in the substantia nigra de-
Fig. 1. Metabolic disfunction in PD
creases within the first 7 days after in vivo modelling in rats using the 6-OHDA and fluoroci-trate-induced neuroinflammation of Parkinson's disease type (Kuter et al., 2019).
There is a tight metabolic coupling between astrocytes and neurons known as the astrocyte-neuron lactate shuttle. Disruptions in this metabolic interaction may impact neuronal health. In PD, alterations in glia-neuron metabolic coupling could compromise the energy support that astrocytes provide to neurons, contributing to neurodegeneration (Segura-Aguilar et al., 2022). Deletion in the Kir6.1 subunit gene of the ATP-sensitive calcium channel leads to worsening of neuroinflammation symptoms in a mouse model of lipopolysaccharide (LPS)-in-duced Parkinson's disease and in cell cultures (Chen et al., 2021). The authors suggest that the effect is associated with astrocyte-neu-ron interaction via the Kir6.1/K-ATP-NF-KB-
C3-C3aR pathway. It has been shown that al-pha-synuclein is transmitted via microtubules in human astrocyte cell cultures (Rostami et al., 2017). It has been shown that in a mixed culture of astrocytes and neurons, alpha-synuclein is transmitted both from neurons to neurons and from astrocytes to neurons, leading to the cell death of the latter (Kuter et al., 2019).
Activated astrocytes in PD may release pro-inflammatory cytokines and contribute to the inflammatory milieu. This inflammatory response can further exacerbate metabolic dysfunction and contribute to the progression of the disease. Astrocytes have been shown to be antigen-presenting cells and play an important role in the activation of T-cells in PD. An a-synuclein-induced inflammatory mechanism has been noted as a result of the transfer of a-synuclein and MHC-II aggregates between as-trocytes through tunnelling nanotubes (Rostami
et al., 2020). Deficiency of neuron-restrictive silencing factor/repressor element 1 (REl)-si-lencing transcription factor (NRSF/REST) enhances the pro-inflammatory function of astrocytes in a model of PD (Li et al., 2020). The role of mast cells in the activation of astrocytes and neurons in PD has been revealed. Neuroinflammation results from the release of IL-33 through activation of ERK1/2, p38 MAPK and NF-kB (Kempuraj et al., 2019). In addition, aq-uaporin 4 (AQP4) modulates the communication of astrocytes with microglia in a cellular model of PD (Sun et al., 2016).
Microglia respond to various signals by undergoing activation, which can be triggered by factors such as the presence of misfolded proteins, oxidative stress, and neuroinflammation. One of the alterations in mitochondrial function within microglia have been noted in PD is mi-tochondrial dysfunction can impair energy production and exacerbate oxidative stress. Dysfunctional mitochondria may release damage-associated molecular patterns (DAMPs), further stimulating the inflammatory response and contributing to neurodegeneration (Chang et al., 2023; Portugal et al., 2022).
There is also evidence that the kynurenine pathway, involved in tryptophan metabolism, has been implicated in microglial activation in PD. Microglia can produce metabolites along this pathway, such as quinolinic acid, which may contribute to neurotoxicity and neuronal damage (Garrison et al., 2018; Heilman et al., 2020; Iwaoka et al., 2020; O'Farrell et al., 2017).
Microglia can also modulate the intercellular transmission of alpha-synuclein. Microglial cells are capable of capturing a-synuclein fibrils, subsequently secreting vesicles containing this protein, which, in turn, are phagocy-tosed by neurons (García-Domínguez et al., 2018; Sznejder-Pacholek et al., 2017). The type of microglial activation plays a significant role in this process. In a study conducted by George et al., LPS -induced microglial activation increased the number of alpha-synuclein aggregates in neurons, while IL-4 treatment reduced the number of microglia with inclusions and prevented neuronal death (George et al., 2019).
Upon activation, microglia undergo metabolic reprogramming to fulfil the increased energy demands associated with their immune functions. This metabolic shift involves alterations in glycolysis, oxidative phosphorylation, and other metabolic pathways. Activated mi-croglia often exhibit heightened glycolysis, a process that rapidly generates energy but is less efficient than oxidative phosphorylation. This shift toward glycolytic metabolism is linked to the production of pro-inflammatory cytokines and ROS by microglia, thereby contributing to the inflammatory milieu observed in PD.
In a study conducted by Lee et al., it was shown that in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) - induced model of Parkinson's disease, the death of dopaminergic neurons was mediated by the activation of NLRP3 inflammasome in microglia (E. Lee et al., 2019). Thus, mice knocked out for nlrp3 and exposed to MPTP showed fewer motor dysfunctions and less pronounced degeneration of dopaminergic neurons compared to wild-type animals in the same model. The other study performed by Sergi et al. also demonstrated increased levels of expression of caspase-3 in the 5-OHDA-induced in vitro model of Parkinson's disease on mixed neuronal-glial cultures (Sergi et al., 2021).
There is evidence suggesting a link between impaired mitophagy in microglial cells and the manifestation of Parkinson's disease symptoms. In their study, Qin et al. demonstrated that the deletion of the autophagy-related gene 5 (atg5) gene exacerbates motor dysfunction and dopa-minergic neuron degradation in the nigrostriatal system in a mouse in vivo model of MPTP-in-duced Parkinson's disease. It has also been shown that suppressing the expression of atg5 in BV-2 microglial culture reduces the ability of microglial cells to adopt neuroprotective M2 polarization in response to IL-4 stimulation. There has also been found a connection between impaired autophagy, IL1B/MIF pro-inflammatory cytokines secretion, and NLRP3-inflammasome activation (Qin et al., 2021).
The other important aspect of metabolic crosstalk with neurons. Glial cells, neurons and mast cells communicate with each other
through a number of signaling molecules: CD40, TLR2, TLR4, PAR-2, CXCR4/CXCL12 and C5a receptor, which promotes migration and activation of glial cells. Metabolites released by activated microglia can influence neuronal function and survival (Kempuraj et al., 2018, 2019).
Metabolic dysfunction stands out as a cardinal feature of PD, particularly affecting dopa-minergic neurons. It has been demonstrated that contamination of neuronal cultures with Labrys neptunia bacteria increases both cytoplasmic and intramitochondrial concentrations of alpha-synuclein oligomers, possibly associated with increased interleukin production, NLRP3 in-flammasome activation, and increased production of ROS (Magalhaes et al., 2023). a-synuclein aggregates disrupt cellular proteosta-sis, impairing protein degradation mechanisms within neurons and fostering the formation of Lewy bodies, characteristic proteinaceous inclusions observed in PD-affected neurons. There is evidence that proteins of the 14-3-3 family inhibit the transmission of pathological alpha-synuclein between cells (Wang et al., 2018). Overexpression of 14-3-3 protein in neurons reduced the toxicity of a-synuclein, but at the same time led to an increase in its secretion by both vesicular and non-vesicular pathways. Conversely, inhibition of 14-3-3 protein resulted in decreased secretion of a-synuclein. Oxidative stress can also influence the aggregation of a-synuclein. In their study, Xiang et al. demonstrated that the post-translational modification of a-synuclein by 4-hydroxy-2-nonenal increases the degree of damage in human dopa-minergic neuron cultures, accompanied by cell death and increased production of ROS (Xiang et al., 2013).
Ketone bodies, synthesized during fasting or through a ketogenic diet, offer an alternative fuel source for neurons, potentially bolstering cellular resilience. Research endeavours in this domain explore the therapeutic promise of dietary interventions. Increasing the energy supply to the neurons with beta-hydroxybutyrate has been shown to be protective (Kuter et al., 2021; Mamelak, 2018; Maurer et al., 2011; Tieu et al., 2003). Calcium homeostasis
emerges as another critical player in PD-related neuronal dysfunction. Dysregulation of calcium homeostasis precipitates excitotoxicity, oxida-tive stress, and mitochondrial dysfunction (Ko-recka et al., 2019; Mamelak, 2018). Aberrant calcium homeostasis may contribute to synaptic changes in neurons as a result of calcium depletion, decreased levels of the synaptic vesicular protein synaptotagmin-1, and decreased energy production due to impaired mitochondrial function (Beccano-Kelly et al., 2023). Additionally, protein aggregation and calcium dysregulation are hallmarks of familial Parkinson's disease (Virdi et al., 2022).
Understanding the intricacies of metabolism within the neurovascular unit cells of the PD's brain is critical to the development of targeted therapeutic strategies. Approaches that address mitochondrial dysfunction, enhance energy metabolism, and promote protein homeostasis in neuronal and glial cells promise to slow the progression of PD and improve the quality of life of affected people. It is important to conduct a detailed study of the role of small molecules -metabolites in the development of aberrant metabolic plasticity of the brain in PD.
Contribution of small molecules to the development of aberrant metabolic plasticity in the CNS
Alterations in metabolic processes in the cells of the central and peripheral nervous systems are observed at early stages of neuro-degenerative diseases (Bell et al., 2020; Borghammer et al., 2010; Deus et al., 2020). Additionally, dynamic changes in metabolite levels have been detected in the striatum and substantia nigra of mice in a model of parkinsonism induced by MPTP (Lu et al., 2018). Lactate can alter the intracellular redox state of cells, as a result of the glycolytic conversion of pyruvate to lactate and back, catalyzed by the enzyme lactate dehydrogenase (LDH): cytosolic LDH-A and mitochondrial LDH-B. The conversion of pyruvate to lactate is necessary to maintain a high cytosolic NAD+/NADH ratio in astrocytes for metabolic activity, pyruvate production through the glycolytic pathway, and subsequent lactate synthesis (Datta & Chakrabarti, 2018).
In separate studies, it is reported that ageing is associated with an increase in lactate levels and alterations in the mRNA expression ratio of LDH-A/LDH-B in the cortex, hippocampus, and substantia nigra of mice (Datta & Chakrabarti, 2018).
Currently, emerging research suggests that disruptions in NAD+ metabolism contribute to the pathogenesis of Parkinson's disease. NAD+ deficiency may be a primary cause of metabolic alterations leading to overall energy production impairment in neurodegenerative diseases (Zagare et al., 2023). Decreased levels of NAD+ in dopaminergic neurons of the brain and muscle tissue accompany ATP production impairments and the development of clinical symptoms in Parkinson's disease (Mischley et al., 2023; Sison & Ebert, 2018). Additionally, NAD+ content in nervous tissue decreases as a result of the inflammatory process (Covarrubias et al., 2020). Thus, the reduction in NAD+ levels may indicate not only a decrease in the activity of NAD+-convert-ing enzymes (nicotinamide phosphoribosyl transferase, poly(ADP-ribose) polymerase, NAD+-glycohydrolase/ADP-ribosyl cyclase, etc.) but also disturbances in glycolysis, lactate metabolism, and mitochondrial dysfunction (Shanahan et al., 2024). Furthermore, glucose deficit, lactate accumulation, and energy depletion are major hallmarks of brain ageing and are associated with morphological/structural changes in ageing brains and neurodegeneration (Camacho-Pereira et al., 2016).
It is worth noting that endogenous metabolites, in addition to their anabolic and catabolic functions, can act as signaling molecules exerting modulatory pleiotropic effects, influencing protein-protein, antigen-antibody, protein-metabolite interactions, altering the conforma-tional structure of protein molecules, and regulating proliferative, inflammatory, neurodegenerative, and immune reactions (Kolotyeva et al., 2023; Kolotyeva & Gilmiyarova, 2019). Pro-inflammatory signals induce cellular metabolic changes characterised by enhanced gly-colysis in the presence of oxygen, similar to the Warburg effect.
Previously, lactate was considered a byproduct of glucose metabolism; however, accumu-
lating evidence now suggests its key role in regulating various biological processes, including cell polarization, differentiation, and effector functions (Li et al., 2023; Magistretti & Al-laman, 2018). The involvement of lactate in regulating intracellular Ca2+ signal transduction has been demonstrated (Sundaramoorthy et al., 2015), as well as its role in cellular energy metabolism, activity of various channels and transporters, myelination, and gene expression (Brooks, 2020; Descalzi et al., 2019; Zhang et al., 2019). It has been established that lactate supports cognitive functions, learning, and the formation of long-term memory (Dienel, 2019; Hertz et al., 2014; Murphy-Royal et al., 2020), and may play a neuroprotective role against ex-citotoxicity (Jourdain et al., 2016). Several studies have shown that short-term cytosolic acidification by compounds playing important roles in cellular metabolism, particularly py-ruvate and lactate, can activate mitophagy and autophagy processes in cells, serving as a protective mechanism in familial PD (Fedotova et al., 2022; Komilova et al., 2022). Furthermore, it has been demonstrated that exogenous and endogenous lactate exert neuroprotective effects in hypoxic-ischemic encephalopathy, suggesting a potential therapeutic approach for ischemia treatment (Deng et al., 2023; Geiseler et al., 2024; Roumes et al., 2021).
In several studies, it has been demonstrated that pyruvate possesses therapeutic potential for the treatment of neurodegenerative diseases. Pyruvate crosses the BBB, enhances neuronal energy supply by participating in the tricarboxylic acid cycle (Suh et al., 2005), increases glycogen content in astrocytes (Shetty et al., 2012), and facilitates the efflux of glutamate from the brain to the blood (Zlotnik et al., 2012). Pyruvate reduces excessive activation of PARP-1 during oxidative stress, thereby restoring energy deficit (Mongan et al., 2003). Anti-inflammatory and antioxidant effects of pyruvate have been demonstrated, attributed to the suppression of the activation of the pro-inflammatory transcription factor NF-kB, expression of TNF-a, IL-6, IL-10, among others (Chakhtoura et al., 2019). Pyruvate prevents dopaminergic neurodegeneration and motor deficits in experimental
Parkinson's disease (Kim et al., 2022). In traumatic brain injury, pyruvate exerts bidirectional neuroprotective and neurodegenerative modu-latory effects by altering mitochondrial activity and motor behaviour in experimental animals (Ariyannur et al., 2021).
In a study analysing transcriptomic data in precursor nerve cells obtained from patients with idiopathic Parkinson's disease (IPD), an elevated level of glycerol-3-phosphate was identified in the cells. Its biosynthesis replenishes the cytosolic pool of NAD+, facilitating energy production through glycolysis. Thus, glycerol-3-phosphate is positioned at the intersection of metabolic pathways and may serve as a potential biomarker for early metabolic changes (Zagare et al., 2023).
It has been shown that lactate levels in the cerebrospinal fluid of PD patients correlate with the clinical progression of the disease and the increase in neurodegeneration biomarkers (Liguori et al., 2022). Astrocytes are recognized as the main producers of lactate in brain tissue, facilitating neuron-astroglial metabolic coupling and the metabolic needs of neuronal cells. Additionally, intermediates are presumed to participate in coordinating the metabolism of cerebral endothelial cells and perivascular as-trocytes. Substantial amounts of lactate are found in the systemic circulation, playing a crucial role in modulating the functional activity of cells comprising the blood-brain barrier (Salmina et al., 2015). High rates of glycolysis with lactate production are present in astrocytes and oligodendrocytes during increased neuronal activity. Monocarboxylate transporters (MCTs) have been shown to localize on cerebral endo-thelial cells, perivascular astrocytes, and other cells of the NVU. They facilitate lactate transport, binding it to specialised lactate receptor GPR81 (also known as HCA1), whose function in the central nervous system is poorly understood (Ahmed et al., 2009; Lee et al., 2001). Experimental evidence has established the presence of GPR81 in neurons, endothelial cells, astrocytes, particularly in the membranes of perivascular and perisynaptic astrocytic processes (Chaudhari et al., 2022; Lauritzen et al., 2014; Morland et al., 2015).
There is emerging research on the role of the GPR81 receptor in mediating brain functions under normal conditions and in brain diseases. It has been demonstrated that lactate, acting through GPR81, participates in brain angiogenesis, promoting brain recovery after hypoxic-ischemic stroke (Chaudhari et al., 2022). Activation of GPR81 has been shown to occur at lac-tate concentrations ranging from 0.2 to 1.0 mM (Ahmed et al., 2010; Dienel, 2012). It has been shown that extracellular lactate levels in the brain can fluctuate from several hundred ^mol/L to 1-2 mmol/L and may possibly increase to 9 mmol/L in pathological conditions (Ahmed et al., 2010; Mosienko et al., 2015).
There is evidence that alterations in lactate production, transport, and reception in brain tissue are among the potential mechanisms underlying neuroinflammation, which is associated with the expression of inflammasomes in effector cells producing pro-inflammatory cyto-kines. Inflammasome activation occurs through stimulation of Toll-like receptors (TLRs), which recognize bacterial LPS and other antigens from bacteria, viruses, thereby initiating a cellular immune response. Chronic activation of TLRs and neuroinflammation contribute to disease progression (Boitsova et al., 2018; I. Deng et al., 2020; Heidari et al., 2022). Existing data indicate that GPR81 inhibits NLRP3 in-flammasome release by activating intracellular adaptor protein ARRB2 and attenuating NF-kB activity, exerting an anti-inflammatory effect (Harun-Or-Rashid & Inman, 2018; Hoque et al., 2014). It has been demonstrated that lactate via GPR81/ARRB2 increases HMGB1 acetyla-tion in macrophages, inducing nuclear translocation of acetyltransferase p300/CBP, leading to increased endothelial permeability (Yang et al. , 2022). Additionally, inhibition of mito-chondrial pyruvate transport, reduced pyruvate oxidation activity enhances NLRP3 inflam-masome activation, thus reprogramming py-ruvate metabolism in mitochondria and cytoplasm should be considered as a novel treatment strategy for inflammatory diseases associ-ated with NLRP3 inflammasomes (Lin etal., 2021).
It has been demonstrated that inflammation induced by LPS can reproduce some characteristics of PD, including extensive microglial activation and selective loss of dopaminergic neurons in the nigrostriatal system. Astrocytes are effector cells in inflammation; however, data on how astrocyte metabolism influences their involvement in inflammatory responses are limited (Komleva et al.., 2021; She et al., 2022). Binding of LPS to TLR4 on microglia induces its activation, leading to neuronal damage. Thus, intrastriatal/intrapallidal LPS injection in experimental animals serves as an adequate in vivo model of PD (M. Liu & Bing, 2011). It has been found that LPS reduces the expression of GPR81 and MCT-1 in endothelial cells and increases lactate concentration in the extracellular space, indicating its role in neuroinflammatory processes altering the structural integrity of the BBB in vitro. It has been demonstrated that elevation of extracellular lactate levels, activation of lactate receptor GPR81 stimulate mitochondrial biogenesis and exert angiogenic effects in a cellular model. Changes in lactate receptor and transporter expression combined with alterations in tight junction protein expression in en-dothelial cells lead to endothelial dysfunction and increased permeability to bacterial and viral pathogens in BBB inflammation models in vitro. In addition, MCT1 has been shown to up-regulate the expression of PFKFB3, activating microglia, promoting a pro-inflammatory effect. Intracerebroventricular administration of exogenous lactate suppressed LPS-induced polarization of microglia, which was accompanied by a decrease in neuroinflammation (Boitsova et al., 2018). The figure 2 shows the aberrant metabolism of NVU cells in PD.
Conclusion and future directions
In summary, Parkinson's disease presents a complex interplay of metabolic dysregulation and neuroinflammation, both of which significantly contribute to its pathogenesis and progression. Metabolic alterations within brain cells, particularly dopaminergic neurons, astro-cytes, and microglia, play pivotal roles in the neurodegenerative processes observed in PD. Mitochondrial dysfunction emerges as a central
feature of PD, leading to decreased ATP production, oxidative stress, and impaired cellular energetics. This dysfunction not only affects dopaminergic neurons but also astrocytes, which are crucial for supporting neuronal function and maintaining brain homeostasis. Moreover, alterations in glucose metabolism, including impaired glucose utilization and insulin resistance, exacerbate neuronal dysfunction and contribute to neuroinflammation. Astrocytes, through the astrocyte-neuron lactate shuttle, provide essential energy substrates to neurons, modulate neurotransmitter levels, and protect against neurotoxicity. Microglia, the resident immune cells of the central nervous system, undergo metabolic reprogramming in response to inflammatory stimuli, contributing to the production of pro-inflammatory cytokines and ROS.
The role of lactate as a signaling molecule and an energy substrate has garnered significant attention, with studies highlighting its involvement in various biological processes, including neuroprotection, cognitive function, and modulation of intracellular signaling pathways. Pyruvate, another key metabolite, exerts anti-inflammatory and antioxidant effects, protecting against dopaminergic neurodegeneration in experimental PD models. Furthermore, alterations in glycerol-3-phosphate levels and lactate concentrations in the cerebrospinal fluid of PD patients underscore the importance of metabolic changes as potential biomarkers for early disease detection and monitoring.
Metabolites are direct reflections of physiologic and pathologic states of the cell and the organism in general. They are attractive candidates for a more complete understanding of disease phenotype, potential biomarkers and therapeutic targets. Metabolomics can provide valuable information on aberrant metabolism of neurovascular unit cells, molecular interactions and metabolic pathways associated with PD. In addition, metabolic dysfunction is a direct result of changes in protein and enzyme activity. Small molecules, as a consequence of protein-metabolite interactions, influence the conformational structure of proteins, receptors, and enzymes, as manifested by altered structural
Fig. 2. The aberrant metabolism of NVU cells in PD
Glucose (Glc) from blood is absorbed by endothelial cells through the GLUT1 transporter and then enters the intercellular space, where it is then absorbed by astrocytes with the help of the same GLUT1. Inside the astrocyte, glucose can be converted into glycogen (GGN), used to support the cell's own needs through glycolysis and the tricarboxylic acid cycle, or it can be converted into lactate (Lac). Enhanced glycolysis in astrocytes is often associated with pathological conditions including neuroinflammation. Lactate from the astrocytes is released into the extracellular space through the astrocytic transporters MCT1&MCT4, from where it is internalized by neurons through the MCT2 transporter. Extracellular lactate interacts with the GPR81 receptor on the surface of neurons, astrocytes, and endothelial cells, which affects the proliferation of these cell types, for example, there is evidence that extracellular lactate activates glycolysis and NLRP3-inflammation formation in astrocytes.
Astroglia cells secrete colony-stimulating factor 1 (CSF1), which interacts with the CSF1R receptor on the surface of microglia, activating the proliferation process. Astrocytes are able to phagocytize MHCII (MHCII-ag) and alpha-synuclein (a-syn) aggregates, and transfer them via transport microtubules to other astrocytes.
Fatty acids (FA), after passing the BBB, are taken up by astrocytes where they are converted into ketone bodies (KB), which in turn are transferred to neurons as an energy source.
Kynurenine (Kyn) enters the microglia being synthesized by monocytes and passing the BBB, or is synthesized within the cell from tryptophan (TRP). One of the pathways of kynurenine metabolism associated with neuroinflammation in microglia is conversion to cytotoxic quinolinic acid (QA).
Glutamine-glutamate shuttle is one of the processes of intercellular interaction between neurons and astrocytes. Astrocytes secrete glutamine (Gln) into the extracellular space, from where it is absorbed by neurons. Inside the neuron, glutamine is converted to glutamate (Glu). After the neuron has secreted glutamate, the astrocyte captures it from the extracellular space. The cycle is closed when glutamate is converted to glutamine inside the astrocyte.
and functional potential. Currently, metabolite profiling in Parkinson's disease is beginning to develop, there are a number of challenges in this field, in particular: identification of unknown metabolites, creation of universally available databases, the influence of individual patient factors such as genotype, lifestyle, diet, disease progression, etc. (Shao et al., 2021).
Overall, understanding the intricate metabolic and inflammatory processes underlying PD pathogenesis, search and identification of metabolites that are specifically altered in PD which will be of great importance for clinical differential diagnosis, provides valuable insights into potential therapeutic targets and ef-
fective treatment options. Targeting these metabolic pathways, presents promising avenues for the development of novel neuroprotective strategies aimed at slowing disease progression and improving the quality of life for PD patients. However, further research is warranted to unravel the complexities of metabolic dysregulation in PD and translate these findings into effective clinical interventions.
Funding Statement
This study is funded by a grant from the Russian Science Foundation (Project number 24-25-00239, https://rscf.ru/project/24-25-00239/).
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