Mechanisms of glutamate metabolic function and dysfunction in vascular dementia

Abstract

As the global population ages, research on the pathogenesis and treatment options for older patients with dementia has become increasingly important. Vascular dementia (VaD), the second most frequent type of dementia, is characterized by vascular impairment caused by inadequate blood supply to the brain. VaD is a complex neurological disorder involving multiple cells and signaling pathways, and its prevention and treatment pose clinical challenges with significant behavioral implications. Glutamate, the most abundant amino acid in the brain, plays a critical role as an excitatory neurotransmitter, impacting cognitive function, learning, and memory. Abnormal glutamate metabolism has been closely linked to dementia, and reduced blood flow to the brain can lead to excessive glutamate accumulation, resulting in neuronal death. This article highlights the connection between VaD and glutamate metabolism, aiming to identify better methods for preventing and treating VaD via regulating glutamate metabolism.

Vascular dementia (VaD), the second most common kind of dementia, is distinguished by vascular impairment caused by insufficient blood flow to the brain. Metabolic syndrome in the brain caused by a large reduction in blood flow to the brain can be deleterious and is a major factor of VaD. Glutamate, the most prevalent amino acid in the brain, is an excitatory neurotransmitter that influences cognitive function, learning, and memory. VaD has been related to abnormal glutamate metabolism, and decreased blood supply to the brain can lead to excessive glutamate buildup, culminating in cell death.

Highlights

• Age‐related changes in metabolism affect various components such as sugars, fats, proteins, and amino acids. Several pathways are involved in glutamate metabolism.

• The link between glutamate metabolism and vascular dementia (VaD) is evident, and modulation of glutamate metabolism may provide new ways to treat and prevent VaD.

1. INTRODUCTION

Vascular dementia (VaD) is a cognitive impairment disease linked to cerebrovascular illness and characterized by clinical symptoms such as memory loss, changes in personality, early gait abnormalities, and urinary incontinence. ¹ VaD denotes the severity of vascular cognitive impairment (VCI), also known as VCID and dementia (VCID). ² Poststroke dementia, multiple infarct dementia, ischemic VaD, and mixed dementia are the four phenotypic types of VaD. ³ In 2018, the VCI Classification Consensus Study (VICCCS) proposed clinically distinct diagnostic criteria for different types of VaD (Table 1). ⁴ In addition, neurological symptoms such as reflex asymmetry, dysarthria (difficulty speaking), parkinsonism, and stiffness are often present. The specific symptoms depend on the type, size, and location of the underlying cerebrovascular pathology. ⁵ The classification of VaD is presented in Table 1.

Table 1.

Diagnosis of various types of VaD.

Types of VaD	Diagnosis
Post stroke dementia	Within 6 months of a stroke, the onset of irreversible cognitive impairment can be immediate or delayed
Multi‐infarct dementia	The presence of multiple large cortical infarcts and their possible role in dementia
Ischemic VaD	Subcortical small‐vessel disease resulting in brain injury, primarily lacunar infarctions and ischemic white matter lesions
Mixed dementia	The co‐occurrence of vascular and other degenerative diseases, such as VCI‐AD and VCI‐Lewy body dementia

Abbreviations: VaD, vascular dementia; VCI‐AD, vascular cognitive impairment‐ Alzheimer's disease.

Alzheimer's disease (AD) has been traditionally associated with dementia, and dementia was classified according to AD criteria until the early 1990s. Distinct disparities exist in the pathomechanisms of AD‐induced dementia and VaD. The primary cause of AD is assumed to be an imbalance between the creation and clearance of beta‐amyloid protein in the brain, which results in an aberrant accumulation of beta‐amyloid, which leads to various neurodegenerative disorders. ⁶ VaD is a cognitive decline caused by neurovascular disease. As people age, cerebrovascular diseases, metabolic diseases, protein lesions, and immune responses can cause vascular damage and further VaD. ⁷ In contrast to neurodegenerative diseases such as Alzheimer's and Parkinson's, VaD is a heterogeneous neurological disorder characterized by localized lesions that reflect the severity of the injury site. ⁸ , ⁹ However, vascular damage is both a major cause of VaD and a cause of AD and other neurodegenerative diseases. Eighty percent of patients with AD (non‐VaD mixed type) have vascular disease, and these vascular risk factors can alter the structure of blood vessels and increase the brain's Aβ and tau burden. ¹⁰ Therefore, the distinction between AD and VaD, especially mixed dementia in the VaD classification, is particularly important for clinical diagnosis. VaD is the second most frequent cause of dementia, accounting for 15%–30% of cases, as the global prevalence of dementia is expected to triple by 2050. ¹¹ Most dementias affect elderly people aged over 80 years. Based on estimations, globally, approximately 391 million people will be in this age range by 2050, from 120 million in 2012. The number of people affected by dementia worldwide is anticipated to rise to 152.8 million by 2050, from 57.4 million in 2019. ¹² The median survival period following a diagnosis of VaD is between 3 and 5 years. VaD incidence in China declined between 2006 and 2010, and the prevalence of dementia increased from 1985–1990 to 2001–2005. ¹³

Senile dementia remains a major focus and challenge in research, both in terms of prevention and treatment. ¹⁴ Clinical imaging is essential for diagnosing VaD and is typically performed using computed tomography (CT) and structural magnetic resonance imaging (MRI), with the main indicators being brain atrophy, white matter hyperintense signals, infarcts, and hemorrhages. ⁴ However, current imaging techniques may not be sensitive or adequate for detecting small vessel disease or assessing vascular status, and differentiating vascular lesions caused by dementias, such as AD, is challenging. An accurate diagnosis of VaD can aid in better and more targeted prevention and treatment of VaD. Thus, imaging studies for VaD diagnosis have recently become a popular topic. Owing to technological advancement, combining single photon emission CT (SPECT) or positron emission tomography (PET) with CT or MRI can detect more subtle changes in blood vessels and blood flow and obtain more detailed, clearer, and functional image information. ¹⁵ , ¹⁶ The newly developed arterial spin labeling technique, which uses blood as the endogenous contrast agent, is a noninvasive, nonionizing perfusion MRI technique that improves image quality while increasing examination safety, and its quantitative detection can help predict VaD onset. ¹⁷ The most effective treatments for VaD include cholinesterase inhibitors such as donepezil, galantamine, and rivastigmine, an NMDA antagonist, memantine, and various traditional Chinese medicines. ¹⁸ , ¹⁹ , ²⁰ Other treatments, such as nonpharmacological interventions and exercise rehabilitation, have also demonstrated promising results. ¹⁸ , ¹⁹ , ²⁰ However, the therapeutic effect of these interventions remains unsatisfactory. Medical management of VaD emphasizes a preventive rather than therapeutic approach, with control of cardiovascular and cerebrovascular diseases and blood glucose and blood lipids, effectively reducing VaD attacks. ²¹ Details of VaD treatments are presented in Table 2.

Table 2.

Treatment of vascular dementia.

Treatments	Details
Pharmacotherapy	Cholinesterase inhibitors and ionotropic glutamate receptor antagonists are generally considered to be the most effective drugs for improving VaD and cognitive function improvement.
Nonpharmacological cognitive interventions	Cognitive training: cognitive stimulation; cognitive rehabilitation
Motor training	The American Academy of Neurology Guidelines recommend physical activity as an intervention for VaD.
Other treatments	Multidisciplinary approach to treating comorbidities (such as motor, psychosocial, and sphincter disorder) and the needs of caregivers.

VaD is a type of progressive cognitive decline caused by damage to blood vessels in the brain that can result from several factors such as high blood pressure, smoking, diabetes, high cholesterol, and other factors compromising blood vessels. The biochemical processes necessary for converting food into energy, collectively known as metabolism, may also be influenced by the same risk factors and contribute to the development of VaD. Mounting evidence suggests that the presence of metabolic syndrome, characterized by higher cholesterol levels, high blood pressure, obesity, and insulin resistance, may increase the likelihood of developing VaD. ⁷ This is because of the damaging effect of metabolic syndrome on blood vessels, which can limit blood flow to the brain, contributing to cognitive decline. Glutamate is a crucial neurotransmitter involved in key brain functions such as learning, memory, and cognition. However, glutamate metabolism disruption can cause neuronal damage, ultimately leading to cell death and promoting VaD onset. Previous reports reveal that altered glutamate metabolism can lead to the production of reactive oxygen species (ROS) and inflammation, enhancing oxidative stress and endothelial dysfunction. ²² These changes can result in decreased blood flow to the brain, neuron damage, and overall cognitive decline, and hence contribute to VaD development. Therefore, this article aims to present a comprehensive review of studies on glutamate metabolism in VaD.

2. ADVANCES IN VAD RESEARCH

2.1. Mechanism underlying VaD

The essence of VaD lies in the dysfunction of the neurovascular unit and abnormal regulation of cerebral blood flow, resulting in damage to cerebral neurons and subsequent dementia, the causes of which include cerebrovascular disease and insufficient cerebral blood supply owing to cardiac causes. In addition to these primary factors, changes in the metabolism of glycolipids and various amino acids have also emerged as novel avenues to study the mechanisms underlying VaD development.

VaD can be caused by various cerebrovascular diseases such as microvascular diseases, atherosclerosis, small arteriosclerosis, and cerebral amyloid angiopathy. ²³ These cerebrovascular diseases cause cerebral hemorrhage, ischemia, and infarction, which impair neuronal function and cause cognitive impairment. The most common causes of VCI are subclinical cerebral white matter lesions, microinfarcts, and multiple infarcts. ²⁴ Poststroke dementia is an important classification in VaD. Stroke is an acute cerebrovascular disease caused primarily by microvascular disease and atherosclerosis, including ischemic and hemorrhagic strokes, with ischemic strokes accounting for most strokes. ²⁵ Immediate or delayed VCI or VaD affects 25–30% of ischemic stroke survivors, and pathologic and imaging studies indicate that VaD accounts for 70% of poststroke dementia. ²⁵ A study comparing 71 patients with stroke with 36 healthy individuals of the same age revealed that patients with stroke experienced extensive structural degeneration of the white matter of the entire brain and gradually developed cognitive problems 3 months after the stroke. ²⁶ Cerebral amyloid angiopathy, a common small vessel disease, can cause VaD by activating vascular damage or inflammatory pathways that impair vascular physiology or increase the risk of stroke. ²⁷ , ²⁸ Acupuncture can help reduce VCI by inhibiting the mir‐93‐mediated toll‐like receptors 4/myeloid differentiation factor 88/nuclear factor kappa‐B inflammatory signaling pathway. ²⁹

The sudden onset of cognitive impairment with neurological impairment in patients who have not experienced cerebral thrombosis for a long time may be due to a cardiogenic stroke. Abnormal heart function is linked to cerebrovascular changes, which can result in asymptomatic infarcts, which have no stroke‐like symptoms but can be detected by neuroimaging or autopsy. Statistically, cardiogenic strokes account for approximately 1/4–1/3 of all strokes and are commonly caused by reduced cerebral perfusion due to cardiac systolic dysfunction, such as heart failure, ischemic heart disease, and atrial fibrillation. ³⁰ Persistent atrial fibrillation leads to VaD at a rate of 1.4%–1.6%. ³⁰ A 35‐year follow‐up study of 148,541 patients with dementia revealed that patients with heart failure had a higher risk of developing dementia than the general population and that the dementia was associated with VaD rather than AD. ³¹

The relationship between metabolism and dementia has received significant attention owing to the changing metabolism associated with aging, which affects various components such as sugars, fats, proteins, and amino acids. At the molecular level, high blood glucose levels raise the body's levels of ROS, and patients with VaD have higher levels of blood lipid peroxidation. ³² , ³³ Abnormal glucose metabolism negatively affects brain function via mechanisms such as glucose neurotoxicity, glycosylation end‐product accumulation, and vascular damage. ³⁴ , ³⁵ , ³⁶ Fatty acids perform significant cellular functions, including energy supply cell and membrane formation and act as precursors for signaling molecules in cellular lipid metabolism. Nevertheless, fatty acid peroxidation can lead to cell death via pyroptosis and ferroptosis pathways, damaging blood vessels and leading to dementia. ³⁷ Moreover, hypercholesterolemia also increases the risk of VaD in older adults, with studies revealing that more than half of patients with stroke have elevated cholesterol levels. ³⁸ , ³⁹

Aside from sugars and lipids, abnormalities in amino acid metabolism can also affect VaD. Amino acid deficiencies negatively affect the body's functioning; however, new research indicates that surplus amino acids can be toxic to cells and are linked to aging and various metabolic disorders. ⁴⁰ , ⁴¹ Shen et al. discovered that patients with ischemic stroke have an accumulation of branched‐chain amino acids and that these excess branched‐chain amino acids exacerbate microglia‐induced neuroinflammation via the AKT/signal transducer and activator of transcription 3/nuclear factor kappa‐B inflammatory signaling pathway. ⁴² In contrast, systemic amino acid homocysteine elevation, also known as hyperhomocysteinemia, is a common disorder of amino acid metabolism that is linked to an increased risk of ischemic stroke. ⁴³ Clinical data suggest that asymmetric dimethylarginine (ADMA), a metabolite of arginine, is associated with cognitive impairment. ⁴⁴ An increase in ADMA stimulates beta‐amyloid secretion and enhances oxidative stress in neuronal cells, as demonstrated by in vitro experiments. ⁴⁵ Glutamic acid is also an amino acid and is one of the most important neurotransmitters in the body. Its abnormal metabolism seriously affects the nervous system.

2.2. Experimental models of VaD

Owing to the late emergence of the concept of VaD and the difficulty of distinguishing between AD and VaD in clinical diagnosis, most clinical applications pertaining to dementia primarily focus on AD, and most treatments for VaD are still in the research stage. ⁴⁶ , ⁴⁷ , ⁴⁸ Therefore, experimental animal models simulating VaD are crucial in research. In this section, we will synthesize the research on VaD modeling. Aging, hypertension, hyperglycemia, hyperlipidemia, and other factors can contribute to VaD. Furthermore, some genetic models suitable for the study of VaD exist, such as spontaneously hypertensive/stroke prone rat, type 2 diabetes mellitus mice, cerebral amyloid angiopathy mice, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy mutant mice. ⁴⁹ However, most recent studies have used surgical modeling of rats or mice combined with cognitive‐behavioral testing. The three types of surgical modeling are transient total cerebral ischemia, primarily 4‐vessel occlusion (4‐VO); chronic total cerebral perfusion deficiency, including bilateral carotid artery occlusion (BCAO) and bilateral carotid artery stenosis (BCAS); and focal cerebral ischemia, primarily middle cerebral artery occlusion (MCAO). ⁵⁰ , ⁵¹ The cognitive behavior of animals can be detected by behavioral experiments such as water mazes, Y‐mazes, T‐mazes, and new object exploration.

4‐VO is a model of total cerebral ischemia achieved by briefly clamping four vessels of the bilateral common carotid and vertebral arteries, resulting in long‐term tissue damage and cognitive deficits. ⁵² Clamping for 5–20 min usually results in acute death of hippocampal neurons, particularly in the CA1 region, resulting in learning and cognitive deficits. ⁵³ Furthermore, transient total cerebral ischemia can be achieved in mice by performing a brief BCAO (also known as 2‐VO) for 5–15 min, which is bilateral common carotid artery clamping. BCAO can cause significant reductions in cerebral blood flow for weeks or even months, which can lead to secondary white matter damage, and significant differences in cognitive‐behavioral tests, such as the water maze, are observed in the first 4–5 weeks after surgery. However, BCAO causes a dramatic decrease in cerebral blood flow and an inflammatory response. ⁴⁷ Kitamura et al. improved this experimental model by implanting ameroid constrictors in the rat's bilateral common carotid arteries. ⁵⁴ BCAS is a mouse model of subcortical ischemic VaD in which partially obstructed microcoils (0.16–0.2 mm) are placed around both carotid arteries, with the diameter of the coils controlling the severity of the obstruction. It causes a similar decrease in blood flow as BCAO; however, the duration of BCAS‐induced decrease in cerebral blood flow is greater than that of BCAO. ⁴⁹ At 5–6 months after BCAS, memory deficits are observed with cognitive‐behavioral testing. ⁵⁵

MCAO is a noncraniotomy and reversible model of acute cerebral ischemia that involves pushing an embolus from the internal carotid artery to occlude the carotid arteries, causing ischemic neurological damage, as well as blocking extracranial vessels such as the left carotid artery, the right carotid artery, and the bifidus vertebral arteries to reduce blood flow to the side branch. ⁵⁶ The steps of the commonly used wire bolus method for preparation of MCAO experiments in rats and mice are as follows: the experimental animals are anesthetized, and an incision is made from the ventral mid carotid cortex to expose the right common carotid artery and the right external carotid artery. The proximal ligature is tied off, a small incision is made in the common carotid artery, and a wire bolus is sutured below the carotid bifurcation into the internal carotid artery approximately 16–20 mm distal to the carotid bifurcation until slight resistance is felt, and the wound is sutured closed. Depending on the time of reperfusion, the animals are re‐anesthetized, their necks are sterilized, a small incision is opened, and a bolus of wire is pulled out to its cephalad side. The excess bolus of wire is cut, the sutures are closed individually, and the wound is sterilized and dressed after surgery. ⁵⁷ , ⁵⁸ The model allows for the establishment of permanent or transient focal cerebral ischemia depending on the timing of reperfusion. ⁵⁹ , ⁶⁰ The results of a study revealed that the mouse underwent a brief 60‐min MCAO occlusion. One week later, water maze testing revealed severe cognitive impairment. ⁶¹ Table 3 highlights the VaD animal models discussed.

Table 3.

The characteristics, advantages, disadvantages and applications of the various VaD animal models.

VaD animal model	Categories	Advantages	Disadvantages	Applications
4‐VO	Transient global ischemia	High ischemic intensity, mimicking clinical brain injury caused by cerebral ischemia.	The surgical maneuvers are relatively complex, complete occlusion of the vertebral artery has a significant impact on cerebral blood flow, and reperfusion is typically incomplete.	For research on anti‐ischemic drugs and cognitive disorders following cerebral ischemia.
BCAO/BCAS	Chronic global ischemia	The operation is relatively simple, making it easier to control reperfusion and detect physiologic changes.	A significant decrease in systemic blood flow, which can easily lead to organ damage.	For the study of anti‐ischemic drugs, cerebral ischemic mechanisms, and postischemic cognitive impairment.
MCAO	Focal cerebral ischemia	No need for a craniotomy, good reproducibility, and the ability to control ischemia and reperfusion time.	Surgery requires some experience and may result in subarachnoid hemorrhage.	Studies on reversible cerebral ischemia and cognitive impairment after cerebral ischemia.

Abbreviations: 4‐VO, 4‐vessel occlusion; BCAO/BCAS, bilateral carotid artery occlusion/bilateral carotid artery stenosis; MCAO, middle cerebral artery occlusion.

3. GLUTAMATE

Glutamate, a nonessential amino acid, can be synthesised by the body through different pathways. The body can convert arginine, proline, histidine, ornithine, and glutamine into glutamate for its various roles. These amino acids constitute approximately 25% of the dietary amino acid intake. ⁶² Glutamate metabolism plays a critical function in protein and nucleic acid synthesis, involving at least 107 regulatory molecules, nine interactors, and three posttranslational modifications. It is also associated with different stress responses. ⁶³ Glutamate is the most abundant amino acid and the primary excitatory neurotransmitter in the central nervous system of vertebrates. Approximately 90% of all synapses in the central nervous system release glutamate; thus, it is important for cognitive, memory, and motor behavior. ⁶⁴

3.1. Synthesis and metabolism of glutamate

The glutamatergic system plays a role in VaD pathogenesis. The glutamatergic synthesis and metabolism machinery is highly complex, with a plethora of potential targets. As a result, a thorough understanding of glutamate synthesis and metabolism is required. These include glutamate production and release, glutamate binding to receptors, and glutamate recovery.

3.2. Synthesis and release of glutamate

Glutamate is the primary excitatory neurotransmitter in the brain and cannot cross the blood–brain barrier unaided. ⁶⁵ However, it can be produced in the brain from cellular glucose metabolism. After cells take up glucose, glycolysis produces pyruvate under the action of phosphofructokinase. Under aerobic respiration, pyruvate undergoes a series of reactions catalyzed by enzymes, such as pyruvate dehydrogenase, to produce acetyl coenzyme A, which then enters the tricarboxylic acid cycle (TCA), generating α‐ketoglutarate. α‐ketoglutarate can produce glutamate in two ways: by reductive amination of α‐ketoglutarate with ammonia catalyzed by glutamate dehydrogenase or via the ATP‐dependent amination of glutamate catalyzed by glutamine synthase (GS) using ammonia as the nitrogen source to produce glutamine. Finally, reductive amination of α‐ketoglutarate with glutamine as the nitrogen donor to produce glutamate is catalyzed by glutamate synthase. ⁶⁶ , ⁶⁷

Glutamate synthesis is closely linked to energy conversion, and glutamate plays an essential role in the metabolism of glucose, fatty acids, and amino acids. ⁶⁸ In addition to glucose metabolism in neuronal cells, astrocytes can take up intracytoplasmic glutamine via a glutamine transporter and convert it to glutamate via the action of glutaminase. ⁶⁹

Glutamate is produced and then transported by glutamate transporters (vGluTs) on synaptic vesicles, which store the glutamate in presynaptic vesicles. ⁷⁰ These vesicles are activated by phosphorylation via protein kinase A, protein kinase C, or CaM kinase II (CaMKII), moved to a release‐ready pool, and fused to the presynaptic membrane. In the presence of the soluble N ethylmaleimide‐sensitive factor attachment protein receptor complex, glutamate, which is Ca²⁺ dependent, is secreted into the synaptic gap mediated by synaptophysin. ⁶⁶ The release of glutamate is a rapid process, with transient concentrations of up to 1 mm and the duration lasting only 1–2 ms before returning to very low nanomolar concentrations. ⁷¹

3.3. Glutamate and its receptors

Released glutamate mediates excitation by binding to ionotropic glutamate receptors (iGluRs) or metabotropic glutamate receptors (mGluRs) on the postsynaptic membrane. iGluRs are ligand‐gated ion channels, providing fast synaptic responses to glutamate, and include α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA), n‐methyl‐d‐aspartate (NMDA), and kainate (KA) receptors (KARs). ⁷² AMPA receptors (AMPARs), enriched at glutamatergic synapses, induce rapid ion channel pore opening and an inward flow of Na⁺ and an outward flow of K⁺ followed by rapid desensitization upon glutamate binding. NMDA receptors (NMDARs) are mainly located in the forebrain. For NMDAR activation, the cosubstrate amino acid l‐glycine binds with its subunit GluN1, while glutamate binds with GluN2. ⁷³ Once NMDARs are activated, they trigger an influx of Na⁺/Ca²⁺ and outflow of K⁺. ⁷⁴ KARs are mainly located in cerebellar and hippocampal synapses and are activated by KA, which is mainly involved in Na⁺/K⁺ flow. ⁷⁵ KA is the amino acid with the strongest excitatory toxicity. When KA is injected into the hippocampus, it exhibits a greater excitability than NMDA and l‐glutamate. ⁷⁶ In contrast to NMDARs and AMPARs, KARs mediate excitatory synapse currents that are relatively smaller in magnitude, and the signals they produce have a slow rise and fall. ⁷⁷ Furthermore, evidence suggests that KARs can be coupled with G protein. ⁷⁸

mGluRs belong to the g protein‐coupled receptor family, providing a slow modulatory response to glutamate. ⁷⁹ The mGluR genes can be classified into three distinct groups. The postsynaptic Group I (mGluR 1 and 5) primarily regulate excitability and plasticity. Both presynaptic and postsynaptic Group II (mGluR 2 and 3) and presynaptic Group III (mGluR 4, 6, 7, and 8) act as autoreceptors by regulating the release characteristics of glutamate in an activity‐dependent manner. ⁸⁰ , ⁸¹ Activation of mGluRs in the central nervous system facilitates or inhibits AMPA and NMDA receptor responses to glutamate by regulating K⁺ and Ca²⁺ ion channels. ⁶⁴ , ⁷⁸ mGluRs play a crucial role in mediating synaptic plasticity and neurotransmitter transmission. The regulation of mGluRs can alter the sensitivity of neurons to excitatory transmitters and affect the metabolism of glutamate.

3.4. Glutamate recovery

After neuronal synapses release glutamate into the cell gap, high‐affinity excitatory amino acid transporters (EAATs) in astrocytes recycle it to maintain intercellular glutamate levels within a relatively safe range. ⁷⁷ The term for these transport proteins is EAAT in humans and glutamate transporter‐1 (GLT‐1) in rodents. ⁸² Excessive glutamate accumulation in the synaptic gap under pathological conditions can lead to neuronal hyperexcitability and cause neuronal cell death. In 1969, Olney demonstrated the neurotoxicity of glutamate when treating mice with monosodium glutamate, which resulted in brain damage. ⁸³

Reduced levels of astrocyte GLT‐1 lead to an accumulation of intercellular glutamate and enhanced excitatory transmission, causing persistent neuropathic pain. ⁸⁴ Abnormal glutamate concentrations have also been associated with various conditions such as epilepsy, ⁸⁵ depression, ⁸⁶ AD, ⁸⁷ and different neurodegenerative diseases. ⁸⁸ , ⁸⁹ , ⁹⁰ Astrocytes take up glutamate and convert it to glutamine rapidly by GS or to α‐ketoglutarate, which enters the TCA cycle, known as the glutamate‐glutamine cycle. ⁹¹ The TCA cycle can provide energy for the metabolism of astrocytes and neurons, with glutamate serving as a metabolic hub. ⁹² Glutamate metabolism involves several pathways (Figure 1).

Figure 1.

Glutamate metabolism involves several pathways. Cells use the tricarboxylic acid cycle (TCA) of glucose to provide energy and materials for glutamate synthesis. Alpha‐ketoglutarate (α‐KG) undergoes a reductive amination reaction with ammonia under the catalysis of GLUD to generate glutamate. However, glutamine synthesis catalyzes the synthesis of glutamine using ammonia as a nitrogen source. Finally, α‐KG and glutamine combine to form glutamate under the catalysis of glutamate synthase. Additionally, astrocytes recycle glutamate from the extracellular space to generate glutamate in the glutamate‐glutamine cycle. The glutamate generated by cells is transported to the synaptic membrane via vGluTs that are dependent on Ca²⁺ and is then released into the extracellular space. The released glutamate activates glutamate receptors on the postsynaptic membrane in the form of a neurotransmitter, exerting excitatory transmission. AMPAR, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole pr‐opionic acid receptor; EAAT, excitatory amino acid transporter; Glu, glutamate; GLS, glutaminase; GLUD, glutamate dehydrogenase; GS, glutamine synthetase; KAR, kainate receptor; mGluR, the metabotropic glutamate receptor; NCX, Na⁺/Ca²⁺ exchanger; NMDAR, N‐methyl‐d‐aspartic acid receptor; PDH, pyruvate dehydrogenase; SNAT, glutamine transporter; TREK‐1, TWIK‐related K channel; VGCC, voltage‐gated calcium channels; vGluTs, vesicular glutamate transporters.

4. GLUTAMATE METABOLISM AND VAD

The inadequate blood supply to the brain caused by cardiovascular disease is one of the important mechanisms underlying VaD, leading to neuronal death and cognitive and behavioral impairment. Moreover, when the brain experiences ischemia and hypoxia due to cardiovascular disease, ATP production is reduced, resulting in abnormal function of the Na⁺/K⁺ATPase (NKA), Na⁺/Ca²⁺ exchange (NCX), and Ca²⁺ATPase plasma pump on the cell membrane. ⁹³ These disrupt ion gradients inside and outside the cell membrane and cause cellular dysfunction, including glutamate metabolism.

Abnormal glutamate metabolism increases glutamate release and inhibits glutamate recycling, leading to excessive intercellular glutamate accumulation and receptor activation as well as tonic cell excitability, known as “glutamate excitotoxicity.” ⁹⁴ , ⁹⁵ Neuronal cells, particularly those in the hippocampus, are sensitive to changes in glutamate levels. Glutamate is an essential excitatory neurotransmitter in the brain, and neuronal functions depend on the transmission of glutamate signals between synapses, which control learning, thinking, and action in humans.

The link between glutamate metabolism and VaD is evident, and modulation of glutamate metabolism may provide new ways to treat and prevent VaD. In this paper, we will review recent studies on glutamate metabolism and VaD.

4.1. Glutamate release and VaD

Glutamate, a neurotransmitter, relies on synaptic function for its release. During mild or early ischemia, synapses may undergo changes such as dendritic swelling and spine reduction; however, chronic inadequate blood supply can result in the complete loss of synaptic structures. ⁹⁶ Numerous studies have indicated that insufficient cerebral blood supply in pre‐VaD leads to increased glutamate release. The primary pathway of neuronal glutamate release is through Ca²⁺‐dependent vesicle release (Figure 2). Under physiological conditions, some Ca²⁺ enters the cell via Na⁺ channels, maintaining normal glutamate release. ⁹⁷ The NCX is an ion channel that removes Ca²⁺ from the cell and is responsible for calcium removal and depolarization under physiological conditions. However, evidence suggests that ischemic conditions trigger the reverse function of NCX, increasing Ca²⁺ inward flow. ⁹⁸ , ⁹⁹ , ¹⁰⁰ Magli et al. synthesized an NCX‐targeted activator that inhibits the reverse function of NCX while activating NCX1 and NCX3 subunits to reduce glutamate release and provide neuroprotection. ¹⁰¹ Molinaro discovered that NCX knockout MCAO mice exhibited increased neuronal vulnerability after ischemic injury. ¹⁰² Moreover, the collapsed ion gradient during the early ischemia stage results in sustained activation of voltage‐gated calcium channels (VGCC), which is another major mechanism of Ca²⁺ inward flow and a significant factor in glutamate release. ¹⁰³ Regulating Ca²⁺ concentration may help maintain stable glutamate metabolism and protect neurons from excitotoxicity. FDA‐approved nimodipine, for example, is an l‐type VGCC channel antagonist used for preventing and treating brain deficits after aneurysmal subarachnoid hemorrhage. ¹⁰⁴ Existing studies have demonstrated that nimodipine is effective for treating VaD. Insulin, ¹⁰⁵ 4,1‐Benzothiazepines, ¹⁰⁶ and CX3CR1 ¹⁰⁷ also inhibit Ca²⁺ inward flow and act as neuroprotective agents. They may be useful as medications to alleviate VaD.

Figure 2.

Abnormal glutamate release in vascular dementia. A significant factor contributing to VaD is insufficient blood supply to the brain. Under conditions of reduced blood supply, neurons are in an energy‐depleted state, leading to abnormal functioning of Na⁺/Ca²⁺ exchanger (NCX) plasma channels and a significant influx of Ca²⁺. As the transport of glutamate vesicles is dependent on calcium ions, excessive calcium ions within the cell result in the over‐release of glutamate. α‐KG, alpha ketoglutarate; Glu, glutamate; GLUD, glutamate dehydrogenase; GLS, glutaminase; GS, glutamine synthetase; PDH, pyruvate dehydrogenase; TCA, tricarboxylic acid cycle; TREK‐1, TWIK‐related K channel; VGCC, voltage‐gated calcium channels; vGluTs, vesicular glutamate transporters.

Furthermore, activation of the two‐pore potassium channel TWIK‐related K channel (TREK‐1), found in many neuronal cells and astrocytes, can mediate rapid glutamate release and increase cognitive impairment due to glutamate toxicity. ¹⁰⁸ TREK‐1 channel activation improves cognitive deficits in demented mice by regulating glutamate metabolism. ¹⁰⁸ Lastly, the volume‐regulated anion channel (VRAC), a chloride channel broadly expressed in cells, is a glutamate‐permeable channel that increases glutamate release under ischemic conditions. ¹⁰⁹ VRAC mutant mice exhibit learning and memory deficits. ¹¹⁰ In conclusion, studies on the effect of glutamate release on VaD are limited. The aforementioned studies have demonstrated that vascular ischemic lesions cause a large release of glutamate; therefore, controlling glutamate release may provide new ideas for VaD treatment.

4.2. iGluRs and VaD

VaD is caused by cerebrovascular injury and insufficient blood flow to the brain, resulting in irregular glutamate metabolism. Glutamate is released from the depolarized presynaptic membrane and activates iGluRs located in the postsynaptic membrane. Abnormal accumulation of glutamate leads to excessive receptor activation, causing more membrane depolarization and Ca²⁺ overload, which commence neuronal death signaling cascades and lead to cognitive, memory, and mobility impairment. Neuroprotective effects come from partially blocking the activation of glutamate receptors. A study on Uncaria sinensis, a herb commonly used among the elderly in Japan for treating cerebrovascular disease and dementia, revealed that it could block the inward flow of Ca²⁺, which otherwise results from glutamate receptor activation. ¹¹¹ It acted as a neuroprotective agent, improved subjective symptom overall improvement scores, psychiatric symptom overall improvement scores, and activity of daily living impairment overall improvement scores in Takashi's research.

AMPARs, or glutamate receptors, are expressed in vascular smooth muscle cells and are involved in the control of blood vessels. Some clinical studies revealed reduced mRNA expression of GRIA1 and GRIA2 subunits of AMPARs in patients with cardiovascular disease. ¹¹² AMPARs may be related to the function of blood vessels. Perampanel, a noncompetitive and highly specific AMPAR antagonist, was recently discovered to inhibit further neuronal damage after ischemia, slow infarction in brain regions, and improve cognitive deficits in MCAO mice. ¹¹³ , ¹¹⁴ In a study, GluA2‐containing Ca²⁺‐impermeable AMPARs (CI‐AMPARs) on synaptic membranes in the hippocampus of MCAO mice were significantly reduced, and CI‐AMPARs inhibited Ca²⁺ inward flow. β‐Caryophyllene inhibited fenestrated postsynaptic currents and reduced neurological deficits, cerebral infarct volume, and cognitive impairments by inducing the translocation of CI‐AMPARs to synaptic membranes of the hippocampus. ¹¹⁵ In a mouse model of VaD, NBQX, an AMPA receptor inhibitor, was administered to the mice, and it significantly lessened axonal degeneration. ¹¹⁶ This suggested that AMPA may play a role in synaptic degeneration under VaD pathology. Fang discovered that hydroxamic acid‐based histone deacetylase inhibitors activate brain‐derived neurotrophic factor (BDNF), which alleviates VaD. ¹¹⁷ This is likely because BDNF enhances the expression of the glua1 subunit on the surface of the nucleus accumbens core AMPAR.

NMDARs are the most permeable to Ca²⁺. ¹¹⁸ They make up the largest subtype of human iGluRs and play a crucial role in neuroplasticity, neuronal development, and learning and memory. ¹¹⁹ Excitotoxicity induced by activation of NMDARs is a major cause of neuronal death in cerebral ischemia. ¹²⁰ Abnormal activation of NMDARs results in excessive intracellular Ca²⁺ and triggers different cell death pathways, such as necrosis, apoptosis, or autophagy. ¹²¹ , ¹²² Ca²⁺associated CaMKII is the primary mediator of glutamate excitotoxicity and oxidative stress‐induced neuronal cell death following ischemic stroke. CaMKII is recruited to the synapse and binds to the NMDA receptor subunit GluN2B at the postsynapse, resulting in T286 autophosphorylation, converting it to autoreactive and regulating synaptic plasticity. CaMKII downregulation leads to memory deficits and impaired cognition in patients with VaD. ¹²³ In addition, chronic neurodegenerative diseases exhibit mitochondrial calcium dysregulation, resulting in dendritic atrophy, with neuroprotective effects frequently resulting from the inhibition of calcium uptake. ¹²⁴ Excitotoxicity resulting from NMDARs also involves the poly (ADP‐ribose) (PAR) polymerase‐1 (PARP‐1) ARP‐1 overactivation, leading to an intrinsic caspase‐independent cell death termed parthanatos. ¹²⁵ In 2011, Shaida discovered Iduna, the first endogenous inhibitor of parthanatos, which blocks PAR polymer signaling in activated NMDARs to produce neuroprotective effects. ¹²⁶ NMDA receptor‐mediated glutamate excitotoxicity is a leading cause of β‐amyloid‐induced neuronal cell death. ¹²⁷ Blocking NMDARs can significantly reduce cell death based on experimental results. ¹²⁸ However, NMDA activation is essential for normal physiological functions, and complete NMDA inhibition is undesirable. Therefore, several NMDA inhibitors are ineffective for clinical applications. Memantine, an FDA‐approved medication for moderate to severe dementia, is a noncompetitive, low‐affinity, open‐channel blocker that selectively impedes excess NMDA receptor activity and protects neurons against glutamate excitotoxicity while not affecting natural physiological processes. ¹²⁹ Moreover, many dementia‐slowing and neuron‐protective medications are linked to NMDARs. Kaixin San, an ancient Chinese herbal formula, significantly reduces NMDA receptor levels to counteract glutamate neurotoxicity and alleviate VaD. ¹³⁰ It also mitigates glutamate accumulation by enhancing ATP content and improving mitochondrial damage through the Shh/Ptch1 signaling pathway. Gutierrez‐Vargas et al. discovered that high doses of atorvastatin restored subunit homeostasis by downregulating GluN2B, improved the adhesion protein complex of NMDARs related to PSD‐95, and boosted cell survival by enhancing Akt activation, enhancing cell plasticity as a result. ¹¹⁹

4.3. mGluRs and VaD

Nerve cells can adjust their susceptibility to injury through inherent physiological mechanisms. mGluR, which can regulate the iGluR response to glutamate, plays a prominent role in such adjustment mechanisms. The number of iGluRs can be modified, which contributes to regulating synaptic efficacy and synaptic remodeling. ¹³¹ In addition to the antagonistic reduction of glutamate receptor activation, endocytosis decreases the number of receptors and reduces glutamate excitability. Studies have demonstrated that mGluR activation has a neuroprotective effect on neurons, particularly in ischemic neuronal cell death. ¹³² mGluR activation promotes endocytosis of NMDA and AMPA by upregulating the ras‐related protein Rab‐5B (RAB5B) gene, which encodes Ras, and downregulating the ionotropic kainate 2 receptor gene, which encodes the GluR6 subunit of the KARs. ¹³³ Patients with VaD have notably reduced levels of synaptic‐related protein expression, particularly low lattice expression in their temporal cortex. ¹³⁴ Clathrin‐mediated endocytosis in the plasma membrane is the principal pathway for receptor internalization. ¹³⁵ It relies on gridin and RAB5B, key molecules that facilitate synaptic vesicle formation, endocytosis, synaptic recycling, and neurotransmitter vesicle release. The Shenzhi Jiannao formula countered glutamate‐induced gridin and RAB5B downregulation and NMDAR1 upregulation, markedly reducing hippocampal neuronal loss. It demonstrated effectiveness in enhancing short‐term and spatial memory. ¹³⁶ This implies that the regulation of iGluR by mGluR is an intrinsic and balanced process. In addition to iGluR regulation, mGluR inhibits Ca²⁺ and activates K⁺, resulting in reduced presynaptic glutamate release. ¹³⁷

The role of IGluRs and mGluRs in VaD is illustrated in Figure 3.

Figure 3.

Excessive activation of glutamate receptors. In VaD, the excessive release of glutamate leads to the over‐activation of glutamate receptors, particularly NMDA receptors, which mediate the influx of Ca²⁺ when activated. Over‐activated NMDA receptors cause a significant influx of calcium ions, subsequently triggering a calcium‐dependent cascade of cell death, which is known as “excitotoxicity.” AMPAR, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid receptor; KAR, kainate receptor; mGluR, the metabotropic glutamate receptor; NCX, Na⁺/Ca²⁺ exchanger; NMDAR, N‐methyl‐d‐aspartic acid receptor.

4.4. Glutamate recovery and VaD

The brain contains glutamate at a concentration of about 10 mM, with most of it being intracellular and approximately 0.6 μM being extracellular. ¹³⁸ Glutamate accumulation is a prephenomenon for numerous pathological responses induced by cerebral ischemia, with its neuronal toxicity perceived as the trigger for ischemic neuronal damage. The stabilization of intercellular glutamate concentrations depends mostly on the Na⁺‐dependent glutamate transporter, found in nerve endings and astrocytes, which collects excess glutamate following release and transports it to endothelial cells for accumulation. ¹³⁹ Inadequate cerebrovascular blood supply results in reduced EAAT function or even reversal, causing a further increase in intercellular glutamate concentrations. ¹⁴⁰ In addition to reduced transporter carrier function, transporter protein expression is also reduced by 50% in the cortex during cerebral ischemia. ⁸² The uptake of glutamate by EAAT relies on the NKA ion pump, which transports sodium and potassium ions into the cell. The function of vGluTs is downregulated when energy depletion or loss of Na⁺ concentration gradient occurs, reducing astrocyte glutamate reuptake and leading to increased extracellular glutamate concentrations. ⁸² The activation of NKA can minimize neuronal damage from glutamate excitotoxicity. ¹⁴¹ , ¹⁴² Administering glutamate via brain at low doses to MCAO rats activates NKA, upregulates GLT‐1 glutamate transporter expression and mitigates glutamate‐induced excitotoxicity and cerebral ischemic injury after reperfusion. ¹⁴³ NKA activation promotes the reassociation of NKA α1 and α2 subunits with GLT‐1 action sites, enhances GLT‐1 function, and protects against tau oligomer‐induced mislocalization of NKA in the cell membrane and decreased glutamate transporter protein expression. ¹⁴⁴ Preventing glutamate toxicity by inhibiting the reversal of glutamate transporter function can be accomplished by inhibiting the reversal of NKA function, which has been demonstrated to have neuroprotective effects. ¹⁴⁵ Additionally, models of cerebral ischemia inhibit glutamate metabolism due to elevated miR‐107 expression, which inhibits GLT‐1 production. Plasma levels of miR‐107 could be utilized as a new biomarker for monitoring neuronal excitotoxicity in patients. ¹⁴⁶

The enzyme GS is primarily found in astrocytes. These specialized cells utilize GS to convert extracellular glutamate into glutamine, a critical process that effectively prevents glutamate excitotoxicity. The glutamate‐glutamine cycle is catalyzed by GS using ATP; however, mitochondria damage affecting astrocytes can impair this metabolic activity. ¹⁴⁷ In cases of cerebral ischemia, activation of the mitochondrial enzyme succinate dehydrogenase (SDH) and the subsequent increase of ROS result in GS carbonylation and proteasomal degradation in astrocytes, leading to disruption in intercellular glutamate‐glutamine cycling. However, baicalein reduces SDH‐mediated oxidative stress, prevents GS loss, and improves glutamate processing by astrocytes. ¹⁴⁸ Ultimately, these actions provide a neuroprotective effect by reducing excitotoxicity and neuronal damage.

The role of glutamate recovery in VaD is illustrated in Figure 4.

Figure 4.

Abnormal glutamate reuptake in vascular dementia. In conditions of cerebral ischemia observed in VaD, the functioning of NCX plasma channels on astrocytes is disrupted, leading to dysfunctional astrocytes. With the reduction in the number of EAAT glutamate transporters, the TREK‐1 and VRAC channels open, leading to the outflow of glutamate. α‐KG, alpha ketoglutarate; EAAT, excitatory amino acid transporters; Glu, glutamate; GLUD, glutamate dehydrogenase; GS, glutamine synthetase; NCX, Na⁺/Ca²⁺ exchanger; TCA, tricarboxylic acid cycle; TREK‐1, TWIK‐related K channel; PDH, pyruvate dehydrogenase; VRAC, volume‐regulated anion channel.

4.5. Other aspects

VaD is caused by changes in cerebral blood flow that result in glutamate accumulation due to insufficient blood supply. Inhibiting glutamate release or increasing its recovery cannot address the underlying energy depletion caused by cerebral ischemia; however, the self‐regulatory capacity of the body can be leveraged to help patients with stroke. Researchers have discovered that administering positive pressure oxygen and hyperbaric oxygen increases glutamate oxaloacetate transaminase (GOT) enzyme activity, which transfers glutamate amino acids to the tetracarbon tricarboxylic acid. ¹⁴⁹ , ¹⁵⁰ The blood/brain glutamate grabbing/scavenging method relies on the natural diffusion of glutamate across the blood–brain barrier, resulting in lower peripheral blood glutamate concentrations and a higher glutamate gradient between the brain and the periphery. Extracellular brain glutamate is then promoted into the bloodstream. Rat experiments have demonstrated that creating a glutamate concentration gradient between the brain and blood allows for efficient transfer of brain glutamate to peripheral blood. ¹⁵¹ The scavenging enzymes glutamate‐pyruvate transaminase (GPT) and GOT scavenge glutamate from the bloodstream, thus increasing the glutamate gradient between the brain and peripheral blood and promoting brain glutamate efflux. ¹⁵² , ¹⁵³ , ¹⁵⁴ These enzymes can reduce brain ischemia‐induced lesions and facilitate cognitive and motor recovery.

One significant advantage of glutamate scavenger enzymes is that they are part of a self‐regulating system in which the rate of glutamate efflux decreases as brain glutamate concentrations decline to restore normal physiological levels. As such, the rate of clearance eventually slows and stops. Unlike glutamate receptor antagonists, these enzymes do not have an impact on glutamate receptors or interfere with normal cellular signaling processes. Furthermore, glutamate scavenger enzymes can be administered immediately after a suspected ischemic stroke and can significantly reduce the risk of stroke‐induced VaD. ¹⁵⁵ By pairing GOT with biomolecules capable of crossing the blood–brain barrier, researchers have effectively enabled targeted delivery of glutamate scavenger enzymes, which can alleviate glutamate accumulation caused by cerebral ischemia and enhance neuronal function to treat VaD. ¹⁵⁶ Aside from GPT and GOT, researchers have evaluated the glutamate‐grabbing properties of riboflavin by conducting in vitro high‐throughput screening based on its ability to interact with GOT. Riboflavin reduced blood glutamate concentrations in a rat model of ischemia and was verified in a randomized clinical phase IIb trial involving patients with stroke. ¹⁵⁷

5. CONCLUSIONS

Glutamate is a critical excitatory neurotransmitter in the brain responsible for numerous cognitive, learning, and behavioral functions. VaD is a multifaceted VCI, and dementia is marked by cognitive, learning, and behavioral impairments. The leading cause of VaD is insufficient cerebrovascular blood supply, which can lead to energy depletion and glutamate excitotoxicity. Research has increasingly scrutinized the relationship between glutamate and VaD. When cerebral blood flow is reduced, an imbalance in the cell's ion channels occurs, resulting in a large inward flow of Ca²⁺. The release of glutamate vesicles is Ca²⁺‐dependent, resulting in a large release of glutamate stored in the presynapse. A large amount of glutamate overactivates receptors such as NMDA to mediate excitation, resulting in “glutamate toxicity.” Furthermore, activation of glutamate receptors during an ischemic state leads to Ca²⁺ imbalance, creating a vicious circle. Meanwhile, the inability of astrocytes to recycle glutamate smoothly during ischemia leads to an excess of intercellular glutamate accumulation. Abnormal glutamate metabolism caused by insufficient cerebral blood flow inevitably worsens the degree of brain damage that existed before VaD. Neural changes occur up to two decades before the onset of cognitive symptoms, thereby emphasizing the need to shift the focus toward markers that enable early detection and treatment. ¹⁵⁸ However, determining whether glutamate accumulation causes vascular injury or abnormal glutamate metabolism as a result of reduced blood flow after vascular lesions is challenging as the two are most likely complementary.

Blocking glutamate signaling alone does not address the neuronal damage induced by glutamate excitotoxicity; however, carefully regulating glutamate metabolism is the most effective strategy for preserving normal physiological function and shielding neuronal activity in the brain. By modulating ion channels such as VGCC, TREK‐1, and VRAC or inhibiting the reverse work of NCX channels, we can control Ca²⁺ levels and prevent excessive glutamate release. Through the selective modulation of glutamate receptors like NMDA, we can also stave off the development of excitotoxicity after glutamate's excessive activation, reducing neuronal death. Additionally, proper management of glutamate transport by astrocytes and glutamate clearance by enzymes such as GOT and GPT is vital in protecting neurons from VaD. In summary, by considering the metabolic process of glutamate and understanding the pathological modifications related to each stage, we can develop a potential therapeutic strategy for dementia. A proposed pathway, based on our study, is illustrated in Figure 5.

Figure 5.

Factors contributing to vascular dementia are depicted schematically. Cerebrovascular disease is the primary cause of VaD, followed by insufficient cerebral blood supply due to cardiac reasons, as well as the accumulation of certain metabolites, such as glutamate, which also promotes VaD.

AUTHOR CONTRIBUTIONS

Jiawen Wang, Yingmei Zhang, Qinghua Li, and Rujia Liao: Conceptualization. Ning Tian, Dongshan Ya, Yanlin Jiang, and Jiaxin Yang: Data curation. Jiawen Wang, Xiaoxia Li, and Xiaohui Lin: Formal analysis. Jiawen Wang, Yingmei Zhang, and Rujia Liao: Figure creation. Jiawen Wang, Yingmei Zhang, Qinghua Li, and Rujia Liao: Writing—original draft. All authors: reviewing and editing the manuscript. All authors have read and agreed to the published version of the manuscript.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

ETHICS STATEMENT

The authors have nothing to report.

Wang J, Zhang Y, Tian N, et al. Mechanisms of glutamate metabolic function and dysfunction in vascular dementia. Neuroprotection. 2024;2:33‐48. 10.1002/nep3.32

DATA AVAILABILITY STATEMENT

All relevant data are within the paper.