Glycolytic dysregulation in Alzheimer’s disease: unveiling new avenues for understanding pathogenesis and improving therapy

Abstract

Alzheimer’s disease poses a significant global health challenge owing to the progressive cognitive decline of patients and absence of curative treatments. The current therapeutic strategies, primarily based on cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists, offer limited symptomatic relief without halting disease progression, highlighting an urgent need for novel research directions that address the key mechanisms underlying Alzheimer’s disease. Recent studies have provided insights into the critical role of glycolysis, a fundamental energy metabolism pathway in the brain, in the pathogenesis of Alzheimer’s disease. Alterations in glycolytic processes within neurons and glial cells, including microglia, astrocytes, and oligodendrocytes, have been identified as significant contributors to the pathological landscape of Alzheimer’s disease. Glycolytic changes impact neuronal health and function, thus offering promising targets for therapeutic intervention. The purpose of this review is to consolidate current knowledge on the modifications in glycolysis associated with Alzheimer’s disease and explore the mechanisms by which these abnormalities contribute to disease onset and progression. Comprehensive focus on the pathways through which glycolytic dysfunction influences Alzheimer’s disease pathology should provide insights into potential therapeutic targets and strategies that pave the way for groundbreaking treatments, emphasizing the importance of understanding metabolic processes in the quest for clarification and management of Alzheimer’s disease.

Introduction

Alzheimer’s disease (AD), a central nervous system disorder, is characterized by the gradual and subtle development of cognitive and memory dysfunction, which ultimately leads to a decline in the capacity to perform daily life tasks, such as learning, working and living ability, and has a serious impact on patient health. AD is the most common age-related dementia disorder characterized by a progressive, irreversible, and highly variable course of cognitive dysfunction associated with neurodegenerative conditions (Scheltens et al., 2016; Feng et al., 2024). AD can present with atypical symptoms from the preclinical to dementia stages, such as attention deficit, and reliable tests are lacking, which often delays clinical diagnosis (Procaccini et al., 2016).

The main pathological features of AD are the formation of senile plaques due to abnormal accumulation of amyloid-β (Aβ) and development of neurofibrillary tangles due to aggregation of hyperphosphorylated Tau proteins (Durairajan et al., 2022; Lucey et al., 2023; Abyadeh et al., 2024; Jin et al., 2024; Ye et al., 2024; Zhang et al., 2024). These pathological changes result in a progressive loss of neuronal connectivity in memory-related brain regions. N-methyl-D-aspartate (NMDA) receptor antagonists, cholinesterase inhibitors, and their combinations have been approved by the Food and Drug Administration (FDA) for treatment of AD (McShane et al., 2019; Liu et al., 2023). Acetylcholine is a key neuromodulator associated with learning, memory, and synaptic plasticity. Therefore, the activity of acetylcholinesterase inhibitors in increasing acetylcholine levels to restore cognitive normalcy has attracted significant research attention. NMDA receptor antagonists are employed to suppress NMDA receptor activity associated with excitotoxicity and cell death mechanisms underlying AD development (Crowell et al., 2006; Wang and Reddy, 2017; McShane et al., 2019; Chen et al., 2021; Pyun et al., 2021; Abdallah, 2024). However, the approved therapies to date only provide temporary symptomatic relief (Shi et al., 2016; Athar et al., 2021; Truong et al., 2022; Table 1).

Table 1.

Drugs for treatment of AD

Target	Drug	Clinical efficacy	Limitation
N-methyl-D-aspartate receptor antagonists	Memantine	Approved for moderate to severe AD	- Gastrointestinal symptoms - Dizziness - Confusion - Headache
Acetylcholinesterase inhibitors	- Donepezil - Rivastigmine - Galantaminel	Approved for mild to moderate AD	- Bradycardia - Syncope
Monoclonal antibodies	- Aducanumab - Lecanemab	Approved for mild AD	- Cerebral edema - Brain hemorrhage
Tau	- Protein phosphatase type 2A - Protein hydrolysis-targeted chimeras	Most of the drugs entered for clinical trials failed in terms of efficacy and only a few remain unproven or display potentially positive trends	No reduction in neurofibrillary tangles has been reported
Against amyloid-β and activate microglia phagocytosis	SHR-1707	A phase I clinical study is underway in China in patients with mild AD	This study is ongoing in China

AD: Alzheimer’s disease.

Several new drugs have emerged in recent years, such as antibodies targeting Aβ that reduce brain fibrillar amyloid deposition. Aβ antibody therapy can effectively suppress disease progression through a number of proposed mechanisms. Firstly, Aβ in peripheral blood is cleared to prevent entry into the brain, leading to disruption of the brain-peripheral Aβ balance and outflow of Aβ. Secondly, the antibody can enter the brain and depolymerize plaques to clear Aβ deposits. Thirdly, the immune complex activates microglia to promote Aβ clearance. Aducanumab was the first antibody drug approved by the FDA for removal of Aβ plaques (Walsh et al., 2021). Lecanemab was more recently approved by the FDA (Reardon, 2023; Figure 1) based on its ability to slow amyloid clearance and clinical decline in early AD (McDade et al., 2022). However, these drugs are associated with serious adverse effects, such as cerebral edema and brain hemorrhage. Further significant concerns include the possibility of additional neuroinflammatory damage by products generated from the combination of Aβ and lecanemab and the prohibitive cost of the drug (Walsh et al., 2022; Cummings et al., 2023; van Dyck et al., 2023).

Figure 1.

Timeline illustrating new drugs developed in recent years incorporating antibodies targeting amyloid-β that reduce brain fibrillar amyloid.

Created with BioRender.com. AChEIs: Acetylcholinesterase inhibitors; AD: Alzheimer’s disease; FDA: Food and Drug Administration.

Treatment strategies for AD involving degradation of tau protein are additionally a significant focus of attention. Targeting of protein phosphatase type 2A, a major brain heterotrimeric tau phosphatase in vivo, offers a potential therapeutic approach to prevent memory deficits and reduce tau pathology observed in AD (McKenzie-Nickson et al., 2018; Taleski and Sontag, 2018; Zheng et al., 2021b). Protein hydrolysis–targeted chimeras have been recently developed as a novel drug strategy for selective degradation of tau protein in cells, whereby the target protein is degraded by the proteasome through ubiquitination (Kargbo, 2019; Schaler et al., 2021; Wang et al., 2021). However, the clinical effects of AD treatment through tau protein degradation remain to be established (Mullard, 2021; Slomski, 2022).

Innate immune cells known as microglia play a significant role in the phagocytosis of Aβ and can serve as intervention target cells. SHR-1707, a monoclonal antibody targeting Aβ, can prevent the assembly of plaques or activate microglia to phagocytose various forms of Aβ, thereby reducing Aβ levels in the brains of AD patients. Clinical studies on SHR-1707 are currently underway in China, although the outcome is yet to be reported (Hu et al., 2023). Phase III clinical trials of these drugs have failed (Honig et al., 2018; Friedman et al., 2021; Swanson et al., 2021; Krafft et al., 2022). Moreover, these drugs only alleviate the symptoms of cognitive dysfunction in AD and are ineffective in preventing cognitive impairment (Dashty, 2013; Boxer and Sperling, 2023). Comprehensive understanding of the fundamental mechanisms underlying AD is essential to facilitate the development of novel drugs that effectively relieve symptoms, limit disease progression, maintain quality of life, and improve cognition, mood, and behaviors of patients.

Several hypotheses have been postulated to explain the cause and effect of AD (Table 2), including cell cycle disturbance, Aβ, neuroinflammation, oxidative stress, and genetic mutations. The majority of hypotheses are based on evidence from molecular or genetic studies. The neuron-centered amyloid cascade hypothesis suggests that missense mutations in the amyloid precursor protein or presenilin 1 promote Aβ production and accumulation, driving AD pathogenesis. Accumulated Aβ oligomers can activate microglia and astrocytes, triggering neuroinflammatory processes, in addition to directly damaging neurons and synapses. However, experiments targeting Aβ clearance to date have failed to achieve validated clinical endpoints. Although AD was discovered more than a century ago, effective primary targets for therapy are yet to be fully elucidated and require further research.

Table 2.

Pathogenesis of AD

Pathogenesis of AD	Aβ cascade hypothesis	Tau protein hypothesis	Neurotransmitter metabolic disorder	Oxidative stress and free radical damage	AD risk gene
Main content	This hypothesis suggests that excessive deposition of Aβ in age spots is the initiating factor for pathophysiologic changes in AD	Neurofibrillary tangles are one of the two major pathological manifestations of AD and their main component is hyperphosphorylated Tau protein	It is widely accepted that loss of cholinergic neurons is a consequence of the pathological process of AD and reduction of acetylcholine causes cognitive dysfunction	During the pathological process of AD, activated glial cells secrete and produce large amounts of inflammatory factors that promote Aβ aggregation and cause damage to tissues and the blood−brain barrier	Apolipoprotein E ε4 is currently the only recognized risk gene for AD, with 40% patients with sporadic AD carrying this allele
Related molecules and proteins	Aβ	Hyperphosphorylated Tau protein	-Glutamic acid -N-methyl-D-aspartic acid receptor	-Interleukin-1 -Tumor necrosis factor-α -Triggering receptor expressed on myeloid cells 2	Apolipoprotein E ε4

AD: Alzheimer’s disease; Aβ: amyloid-β.

Normal brain function utilizes 19%–20% of overall energy. The main energy substrate of the brain is glucose. Aerobic glycolysis is physiologically enhanced for brain function and decreases with aging. Deleterious mitochondrial dynamics alter glucose utilization pathways and are currently recognized as important players in the occurrence and development of AD (Ye et al., 2017; Ke et al., 2019; Rostagno, 2022). Studies based on bioenergetics theories have formulated a novel hypothesis regarding AD metabolism. Age-related mitochondrial dysfunction, metabolic changes in oxidative phosphorylation pathways, and increased production of reactive oxygen species are proposed to be key factors leading to neuronal dysfunction and death in the brain (Yin et al., 2016; Ashleigh et al., 2023). The above pathways may represent key pathogenetic mechanisms, accounting for 95% of sporadic AD cases. Clearly, impairment of energy metabolism serves as an important pathogenic determinant of AD. In addition, normal metabolic processes of neuronal glial cells are altered in AD (Procaccini et al., 2016; Chhetri et al., 2022).

Metabolic changes and defects in neurological disorders are prevalent not only in neurons but also astrocytes, microglia, and oligodendrocytes (Baik et al., 2019; Wang et al., 2020; Chamberlain et al., 2021; Farina et al., 2023). Elucidation of abnormalities in the glycolytic pathway in AD brain cells should aid in the development of innovative approaches for exploring etiology and identifying novel therapeutic targets for AD. Glycolysis plays an important role in glial cell metabolism and is also required for neuronal function upon activation. Recent studies have shown that glycolysis is significantly altered in the brain in association with the onset of AD. Therefore, improved understanding of changes in the glycolysis process should facilitate the elucidation of mechanisms governing the occurrence of AD (Tang, 2020; Traxler et al., 2022).

Retrieval Strategy

We searched the PubMed database online for articles from inception of the database until April 24, 2024, mainly focusing on those from the most recent 2–4 years. A total of 1890 articles were screened of which 175 were used as references. The following combinations of search terms were employed to maximize specificity and sensitivity: “Alzheimer’s disease,” “advertising,” “glycolysis and neuronal metabolism,” “glucose metabolism,” “glial cells,” “neurodegenerative diseases,” “neurons,” “astrocytes,” “oligodendrocyte,” and “microglia.” Terms were selected to retain only research exploring the relationship between altered glycolysis of nervous system cells and the pathogenesis of Alzheimer’s disease. Articles lacking experimental data on the relationship between altered glycolytic metabolism and AD pathogenesis and those that did not specify the publication year and author were excluded.

Glycolysis in the Brain

Glucose metabolism is the primary source of energy and glycolysis uses a combination of enzymes and co-enzymes to catalyze the metabolism of glucose to pyruvate or lactate (Figure 2). The conversion of glucose to pyruvate results in the generation of adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide by the actions of hexokinase (HK), phosphoglycerate kinase, and pyruvate kinase (Chandel, 2021). One molecule of glucose produces two molecules of ATP during glycolysis, which occurs exclusively in the cytosol. Three main rate-limiting enzymes catalyze irreversible reactions in the glycolytic pathway, specifically, HK, phosphofructokinase (PFK), and pyruvate kinase. Among these enzymes, PFK is the key rate-limiting factor (Hipkiss, 2019). The products of glycolysis are further utilized by oxidative phosphorylation and that glycolysis is widely recognized to play an essential role in changes in the energy composition of cells.

Figure 2.

Schematic diagram of the glycolysis pathway and key enzymes.

Created with BioRender.com. ADP: Adenosine diphosphate; ATP: adenosine triphosphate; NADH: nicotinamide adenine dinucleotide hydrate.

Glucose serves as an energy substrate for the brain. Neurons utilize glucose via two stages, specifically, glycolysis and mitochondrial oxidative phosphorylation. A recent study has demonstrated the occurrence of aerobic glycolysis in the cytoplasm of neurons and oxidative phosphorylation at the nerve terminals (Wei et al., 2023). During brain activity, the energy requirements of neurons increase and the rate of glycolysis temporarily exceeds that of mitochondrial oxidation. Studies using biosensors related to metabolism in the brain of awake normal mice showed that in rapid response to increased energy demand, neuronal glycolysis temporarily outpaced mitochondrial oxidative metabolism (Dienel and Rothman, 2019; Li et al., 2023; Wei et al., 2023). Significant enhancement of glycolysis during brain activation in humans has been detected with positron emission tomography/computed tomography using a radioactive isotope. Compared to oxidative phosphorylation, glycolysis produces less ATP, but can rapidly generate ATP, which meets the urgent energy requirement during increasing brain activity (Dienel and Cruz, 2016). Given the significant role of nerve terminals in neuronal function, this finding suggests that different neuronal sites metabolize glucose to produce energy via distinct pathways, with oxidative phosphorylation serving as a key modality.

Astrocytes, the most widely distributed glial cells in the brain, utilize glycolysis to meet their energy requirements. These cells rely on glycolysis for energy production owing to the presence of free mitochondrial complex I, which results in limited oxidative phosphorylation. As a result, astrocytes produce increased levels of mitochondrial reactive oxygen species to generate more energy to meet their needs, thereby influencing the hypoxia-inducible factor cascade reaction and expression of key enzymes to promote glycolysis (Jimenez-Blasco et al., 2020). The astrocyte–neuron lactate shuttle (ANLS) hypothesis suggests that during nerve conduction and synaptic transmission, glutamate, a chemical released by neurons, travels to the surrounding astrocytes and stimulates a series of metabolic processes, including glucose uptake, glycogenolysis, and glycolysis. Additionally, lactic acid produced by the glycolytic pathway of the astrocytes maintains neuronal plasticity and aids in the maintenance of normal brain function (Barros and Weber, 2018). Astrocytes deliver glycolytically produced lactate to neurons for energy utilization via the ANLS (Medel et al., 2022). The energy requirement of microglia for immune function is met by oxidative phosphorylation. Microglia indirectly supply energy to neurons, but the release of enormous amounts of lactate from microglia in the activated state is likely to be recycled locally by neurons. The primary method for energy metabolism in oligodendrocytes is glycolysis. Mature oligodendrocytes rely on glycolysis to produce ATP, since these cells are unable to assemble stable mitochondrial cytochrome c oxidase (Fünfschilling et al., 2012; Philips and Rothstein, 2017). Oligodendrocytes supply lactate to the surrounding axons and maintain myelin and long-term axonal integrity, a process associated with the release of glutamate from neurons (Eraso-Pichot et al., 2018). Overall, glycolysis is a more direct source of ATP than oxidative phosphorylation and rapidly replenishes ATP upon impairment of mitochondrial function, serving as a critical means of energy production for the brain. Thus, glycolysis serves as an important metabolic mode for different cell types in the brain (including neurons, microglia, astrocytes, and oligodendrocytes) and is essential for maintaining normal brain activity. In addition to neurons, other cell types replenish energy via glycolysis, thus forming an extensive energy metabolic network in which glycolysis plays a key role (Table 3).

Table 3.

Changes in glycolysis among different cell types in Alzheimer’s disease and related molecules or enzymes

Cell type	Neuron	Microglia	Astrocyte	Oligodendrocyte
Glycolytic change	Increased	Increased	Diminished	Diminished
Related molecules or enzymes	- Pyruvate kinase - Hexokinase - Phosphofructokinase	- Lactate dehydrogenase B-chain - Pyruvate kinase M2 - Hexokinase 2 - Glyceraldehyde-3-phosphate dehydrogenase	- Monocarboxylic acid transporter 1 - Monocarboxylic acid transporter 4 - 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3	- Monocarboxylic acid transporter - Phosphofructokinase - Phosphoglycerate mutase - Pyruvate kinase - Hexokinase

Glycolysis in Alzheimer’s Disease

Enhanced neuronal glycolysis in Alzheimer’s disease

Neurons need to maintain ATP homeostasis in axons to ensure normal function (Chamberlain et al., 2021). AD is characterized by damage to the mitochondria and glucose metabolism (Barros and Weber, 2018; Butterfield and Halliwell, 2019). A decline in glucose metabolism is an early event in AD, occurring before the manifestation of symptoms and clinical diagnosis. Positron emission tomography/computed tomography brain imaging studies have confirmed a significant decrease in glucose metabolism in the brains of patients with AD (An et al., 2018; Hirata et al., 2023). In postmortem brain samples of patients with early AD, a marked increase in the activities of key enzymes in glycolysis in the frontal and temporal cortex areas of cognitive capability is reported. Furthermore, modulation of glucose uptake via overexpression of the glucose transporter (GLUT) or metformin could attenuate the attention deficit phenotype in a Drosophila model of Aβ toxicity (Niccoli et al., 2016; Baik et al., 2019).

Glucose transporters are a group of key gating proteins responsible for the entry and exit of glucose into and out of brain tissue. In AD patients, the levels of GLUT1 and GLUT3 are reduced (Wang et al., 2019), along with a decrease in oxidative phosphorylation in mitochondria. Earlier studies have shown that the tricarboxylic acid cycle and electron transport chain activities of mitochondria-related enzymes are diminished or eliminated (Hashimoto et al., 2012; Butterfield and Halliwell, 2019). In AD mice, levels of nicotinamide adenine dinucleotide phosphate, a key compound used to drive the mitochondrial electron transport chain, are reduced owing to mitochondrial dysfunction. This reduction of energy supply is partly compensated by glycolysis. A recent study has demonstrated reduced mitochondrial metabolic function and upregulated glycolytic pathways in AD neurons (Mullard, 2021). Pathological isoform switching of the key glycolytic enzyme, pyruvate kinase, confers metabolic and transcriptional alterations in AD neurons. Oxidative modification can induce a decrease in the activity of enzymes involved in glucose metabolism, which is the primary cause of inefficient glucose utilization, along with a shift in metabolism from oxidative phosphorylation to glycolysis in AD patients (Traxler et al., 2022). The Wnt signaling pathway plays a critical role in the metabolic transition from oxidative phosphorylation to glycolysis in neurons of AD. A previous study by Cisternas et al. (2019) reported that in an AD model of transgenic mice, Wnt agonists activated HK and PFK in cortical and hippocampal neurons and enhanced glucose metabolism, which significantly improved cognitive ability. A number of studies in the literature suggest that Wnt signaling stimulates glucose utilization in neurons via the glycolytic pathway to meet the high energy demands of cells in AD brain (Cisternas et al., 2016; Inestrosa et al., 2021; Martínez and Inestrosa, 2021; Yu et al., 2022; Kostes and Brafman, 2023). These findings offer novel prospects for improving cognitive function in AD brain through alterations in glycolysis.

Diminished glycolysis in astrocytes in Alzheimer’s disease brain

Resting oxygen consumption is ~87% for neurons and 13% for glial cells. As the most widely distributed cell type in the brain, astrocytes outnumber neurons and play a key role in functional maintenance of the central nervous system (Sakuma et al., 2024). Through extension and complex morphological changes, astrocytes can fill in the spaces between neuronal bodies and protrusions and additionally participate in construction of the blood–brain barrier (Wang et al., 2022b).

Additionally, astrocytes secrete neurotransmitters and express their receptors that contribute to physiological effects, transformation of exogenous compounds, regulation of the ionic microenvironment around neurons, and coordination of normal neuronal function. In the brain, astrocytes absorb glucose to provide a constant supply of energy for activity, primarily through glycolysis (Bolaños et al., 2010; Bolaños, 2016; Magistretti and Allaman, 2018; Jimenez-Blasco et al., 2020; Traxler et al., 2022). The ANLS theory suggests that glucose from capillaries is taken up by astrocytes via GLUT1 (Muraleedharan et al., 2020). Following uptake, glucose is either stored as glycogen or undergoes glycolysis to pyruvate in astrocytes. Pyruvate translocates to mitochondria or is converted to lactate that is excreted via monocarboxylic acid transporters 1 or 4 (MCT1/4) and transported to neurons via MCT2. In neurons, astrocyte-derived lactate is converted back to pyruvate, which enters the mitochondria to produce ATP (Fernandes-Costa et al., 2022; Sakuma et al., 2024). According to the ANLS (Figure 3), astrocytes serve as a vital component of the blood–brain barrier, absorbing glucose from peripheral capillaries via GLUT1.

Figure 3.

The astrocyte–lactate–neuron shuttle.

Glucose is absorbed by astrocytes and neurons via GLUT1 and GLUT3, respectively. After absorption, glucose is stored in astrocytes as glycogen or undergoes glycolysis to generate pyruvate. In astrocytes, pyruvate is translocated to mitochondria or converted to lactate, which is excreted from astrocytes via MCT1/4 and transported to neurons via MCT2. In neurons, lactate is converted back to pyruvate, which enters mitochondria to produce ATP. Created with BioRender.com. ADP: Adenosine diphosphate; ATP: adenosine triphosphate; GLUT1: glucose transporter 1; GLUT3: glucose transporter 3; LDH1: lactate dehydrogenase 1; LDH5: lactate dehydrogenase 5; MCTs: monocarboxylic acid transporters; NAD⁺: nicotinamide adenine dinucleotide; NADH: nicotinamide adenine dinucleotide hydrate.

6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) is abundantly expressed in astrocytes (Radford-Smith et al., 2022) and serves as a key activator of glycolysis. In AD, astrocytes upregulate glycolytic pathways to compensate for the energy deficits of neurons induced by Aβ. Glucose uptake and lactate production are reduced and the glycolytic pathway is impaired in AD (Le Douce et al., 2020; Zheng et al., 2021a; Xie et al., 2023). Products of gut flora metabolism have been shown to promote glycolysis in astrocytes and improve cognitive functions (Cuervo-Zanatta et al., 2023). Apolipoprotein E is a class of risk-associated genes in AD with three isoforms, of which type E4 is the most prevalent modulator of AD (Lozupone and Panza, 2024). In apolipoprotein E type 4 astrocytes, glucose flux for early glycolysis is the lowest among the three isoforms, indicating reduced glycolysis-related gene and enzyme activities in AD (Williams et al., 2020; Martens et al., 2022). Astrocytes are reported to internalize Aβ via the type A scavenger receptor, which affects the rate of glycolysis through the phosphatidylinositol 3-kinase pathway (Allaman et al., 2010). Aβ concomitantly suppresses the expression of glycolysis-related enzymes through inducing a decrease in hypoxia-inducible factor 1α. In AD, Aβ triggers astrocyte proliferation, disrupts cellular glycolysis, reduces astrocyte–lactate–neuron shuttle efficiency, and affects neuronal function. Induction of overexpression of MCT2 and MCT4 to improve the lactate shuttle ability reduced cognitive impairment in AD model mice in earlier studies (Zhang et al., 2018; Lu et al., 2019; Zhao et al., 2022).

Effects of astrocytes with altered glycolysis on neurons in Alzheimer’s disease

As discussed above, glycolysis is key component of the metabolism of astrocytes, which are widely distributed in the brain. Astrocyte cells are closely associated with neurons and regulate synapse growth, neuronal differentiation, and the normal presence of neurons via secretion of neurotrophic factors (Wheeler and Quintana, 2019). A variety of receptors that transduce signals via the second messenger system are expressed by astrocytes (Bazargani and Attwell, 2016; Yu et al., 2020; Zhou et al., 2021). Moreover, these cells release and clear neurotransmitters and modulate the extracellular ionic microenvironment to regulate synaptic transmission (Ben Haim and Rowitch, 2017). Neurons and astrocytes are tightly coupled units of energy metabolism in the brain. Neurons consume large amounts of ATP to perform their physiological functions. Through ANLS, astrocytes provide the metabolic substrates needed for neurons to sustain high levels of activity (Chen et al., 2023; Figure 3). Elevated levels of extracellular K⁺, glutamate uptake, and intracellular Ca²⁺ trigger lactate release from astrocytes. In addition, astrocytes exert distinct effects on neurons depending on the expression of connexin and channel proteins. Activation of type A1 astrocytes suppresses glycolysis, which reduces the expression of connexins, alters cell sizes, and limits interactions with neurons, resulting in a 50% decrease in the number of excitatory synapses. Moreover, astrocytes phagocytose excitatory synapses and augment the activity of inhibitory synapses (Lee et al., 2021a; Byun et al., 2023). Simultaneously, neuronal axonal regeneration is suppressed by the inhibitor chondroitin sulfate proteoglycan secreted by type A1 astrocytes (Stogsdill et al., 2017; Zhang et al., 2020a).

Metabolic dysfunction of astrocytes is associated with AD (Mashima et al., 2018). Fibroblast growth factor 21, which regulates the energy metabolism of astrocytes through ANLS to exert neuroprotective effects (Zheng et al., 2021a), is downregulated in AD. Increased expression of this factor has been shown to ameliorate brain metabolic defects and Aβ-induced cytotoxicity (Sun et al., 2020). In AD, Aβ triggers cellular stress via phosphorylation of dynamin-related protein 1 and disruption of mitochondrial structures, leading to swelling and fragmentation, which impairs astrocyte function, promotes dysregulation of glycolysis, and impedes clearance of Aβ (Galea et al., 2022; Zyśk et al., 2023). Recent experiments suggest that upregulation of glycolysis can reduce Aβ load (Shan et al., 2023). Suppression of glycolysis is associated with increased mitochondrial activity and decreased rates of lactate production as well as MCT1 expression. Lactate is transferred from astrocytes to neurons via MCTs. Owing to downregulation of MCT1 and decreased lactic acid production, the energy available to neurons is reduced. In addition, astrocytes release inflammatory factors that damage peripheral neurons, reduce synaptic plasticity via complement component 1q, and inhibit neural signaling (Jiang and Cadenas, 2014; Al-Ghraiybah et al., 2022; Ardanaz et al., 2022; Dejanovic et al., 2022; Galea et al., 2022). L-serine is a precursor of D-serine, a co-agonist of the NMDA receptor, which is implicated in synaptic plasticity. In AD, defective astrocyte glycolysis leads to impaired L-serine synthesis, and consequently, disruption of synaptic plasticity (Le Douce et al., 2020). Adrenergic transmitters are reduced in neurons in AD, which affects the activity of glycolysis-regulating receptors on the surface of astrocytes, leading to an overall decrease in astrocyte glycolysis (Zorec and Vardjan, 2023).

Enhanced glycolysis in microglia in Alzheimer’s disease

Microglia are immune cells in the brain (Wang et al., 2023; Han et al., 2024). In gray matter, microglia are mainly located near the cell bodies of neurons or around small blood vessels and are additionally present in white matter. Microglia in the brain account for 5%–10% of all glial cells and require considerable energy to perform their immunological functions, including proliferation, migration, and phagocytosis (Aguzzi et al., 2013; Li et al., 2021). Energy is normally supplied to microglia via oxidative phosphorylation, and upon activation for immune functions, these cells switch from being primarily supported by oxidative phosphorylation to glycolysis. Activated microglia promote glycolysis and suppress respiration. A number of studies have shown that glycolysis is actively involved in microglial activation and inhibition of glycolysis can ameliorate associated neuroinflammation (Pellerin and Magistretti, 2012; Cheng et al., 2021; Fairley et al., 2023; Yang et al., 2023). Glycolysis influences the expression of pro-inflammatory genes at both transcriptional and post-translational levels. Pyruvate kinase M2 (PKM2), a key glycolytic enzyme, has been shown to promote the activation of microglia and enhance microglial phagocytosis. Upon knockdown of PKM2 in mice, activation of microglia and loss of synapses were significantly reduced in a study by Lu et al. (2021). Activated microglia require considerable energy. As a result, neuronal energy supply is reduced when the brain glucose supply is persistently low.

Metabolic dysfunction of microglia is closely linked to AD (Xia et al., 2022; Sangineto et al., 2023; Figure 4). Under conditions of AD, the predominant process of energy metabolism in microglia shifts from oxidative phosphorylation to glycolysis (Baik et al., 2019), accompanied by upregulation of GLUT1 and GLUT4 (Wang et al., 2019). Moreover, expression of numerous genes involved in glycolysis is increased due to decreased glucose metabolism. Sequencing data have revealed elevated mRNA levels of HK2, PKM2, and glyceraldehyde-3-phosphate dehydrogenase during AD progression. HK, a key enzyme of glycolysis in the cytoplasm of microglia, enhances phagocytosis and its immunoreactivity is independent of metabolic activity. Due to the presence of Aβ, recruitment of HK to mitochondria in microglia induces a shift in the metabolic mode towards glycolysis and reduces phagocytosis. In AD mice, the shift from oxidative phosphorylation to glycolysis in microglia could be reversed by the inhibition of hypoxia-inducible factor-1 alpha, which ameliorated cognitive decline (Zhang et al., 2017; Fairley et al., 2023). Furthermore, in AD mouse brain, elevated lactylation of histones in microglia near Aβ is reported to drive a positive feedback loop of lactate/PKM2/glycolysis that promotes the pathology of attention deficit disorder (Bolaños et al., 2010; Pan et al., 2022). HK2, another key enzyme in glycolysis, appears to play a crucial role in triggering alterations in microglial metabolism (Leng et al., 2022; Ma et al., 2022; Codocedo et al., 2023). Inhibition of HK2 promotes the phagocytosis function of microglia, enhances the clearance ability of Aβ, and improves the cognitive function of AD mice (York et al., 2021; Leng et al., 2022). Thus, enhanced glycolysis is strongly associated with microglial immune function under AD pathological conditions. The identification of biomarkers of metabolic changes in microglia should offer valuable insights that contribute to the development of innovative approaches for effective AD diagnosis (Sangineto et al., 2023).

Figure 4.

Overactivated microglia trim neuronal dendritic spines in Alzheimer’s disease.

Microglia are overactivated, releasing substantial amounts of inflammatory factors (IL-6, TNF-α, and NO). Simultaneously, the ability of microglia to phagocytose Aβ is reduced and that to prune dendritic spines overactivated, leading to neuronal loss. Created with BioRender.com. Aβ: Amyloid-β; IL-6: interleukin-6; NO: nitric oxide; TNF-α: tumor necrosis factor-α.

Altered microglial glycolysis in Alzheimer’s disease affects neurons

Microglia maintain brain homeostasis by removing myelin and cellular debris from neurons. These cells can shape neural circuits by releasing soluble factors that interact with neurons (Choi et al., 2020). For example, microglia regulate the production of cytokines, such as tumor necrosis factor-α, that are involved in synaptic plasticity by activating synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. The chemokine C–X3–C motif chemokine ligand 1 produced by neurons binds to microglial chemokine C–X3–C motif receptor 1 to achieve neuronal regulation. Neurons are additionally capable of releasing exosomes to modulate microglial activation (Xian et al., 2022). The reciprocal regulation of microglia and neurons influences synaptic plasticity and functional homeostasis in the brain (Marinelli et al., 2019).

Single-cell sequencing revealed elevated levels of proteins involved in glycolysis in microglia under AD conditions, including lactate dehydrogenase B-chain, pyruvate kinase M, and 3-phosphoglyceraldehyde dehydrogenase (Johnson et al., 2020). Elevated Aβ levels stimulate microglia and enhance their glycolytic metabolism (Pan et al., 2022), leading to an energy crisis in neurons due to the high energy demand of this incomplete metabolic pathway. Consequently, neuronal function is severely compromised by both energy deficiency and inflammatory factors released by activated microglia (Meng et al., 2020; Wang et al., 2024). Enhanced glycolysis can be accompanied by macrophage polarization, along with high expression of cluster of differentiation 68 on the surface of macrophages and activated microglia (Jeong et al., 2019; Zhang et al., 2023; Liu et al., 2024). In AD, glycolysis promotes activation of microglia, enhancing microglial phagocytosis and elimination of Aβ with simultaneous release of inflammatory factors (Leng et al., 2022; Codocedo et al., 2023). Interestingly, inhibition or semi-knockout of HK2 could enhance microglial phagocytosis and delay disease progression in 5×FAD mice, while complete deletion of HK2 did not ameliorate progression of AD (Leng et al., 2022; Codocedo et al., 2023). Triggering receptor expressed on myeloid cells 2 (TREM2), a protein associated with microglial phagocytosis, plays a dual and opposite role in the activation state of microglia, suggesting that the different effects of HK2 on the phagocytic function of microglia may be related to TREM2 (Rachmian et al., 2024). Complement (such as complement protein 3 and complement component 1q) and microglia mediate synaptic loss in the early stages of AD (Hong et al., 2016). Microglial glycolysis is enhanced in AD. The complement activity of immune cells is required to induce their metabolic reprogramming, including increased glycolytic flux (Kunz and Kemper, 2021). Enhanced glycolysis promotes the synaptic phagocytic activity of microglia and synaptic pruning, resulting in loss of neuronal synapses and neuronal dysfunction (Lu et al., 2021; Figure 4).

Altered microglia and astrocyte glycolysis in Alzheimer’s disease reciprocally affect activation states

Under normal conditions, astrocytes and microglia are closely linked and regulate the functions of each other through secreted factors (McAlpine et al., 2021). Astrocytes express synapsin II and cellubrevin, which mediate neuronal glutamate and neuropeptide Y secretion to maintain neuronal function (Schwarz et al., 2017; Pathak and Sriram, 2023). Moreover, astrocytes mediate synapse elimination and play an important role in neuronal homeostasis by removing dysfunctional or dead synapses (Park and Chung, 2023; Tzioras et al., 2023).

In AD, microglia and astrocytes undergo metabolic reprogramming. PKM2, PFKFB3, and interleukin-1β are highly expressed in microglia, inducing the shift towards glycolysis. Suppression of GLUT1 in astrocytes could induce a decrease in glycolysis (Souza et al., 2015; Mela et al., 2020; Pan et al., 2022; Wang et al., 2022a; Zhang et al., 2022). Apolipoprotein E is a key risk gene for AD mainly expressed in astrocytes and associated with decreased glycolysis. ApoE participates in the formation of Aβ oligomers and is part of an important feedforward loop between astrocytes and microglia (Deng et al., 2023). Astrocytes and microglia near Aβ plaques contain more synaptic proteins, resulting in synaptic degeneration and removal of functional synapses. Through inhibition of milk fat globule epidermal growth factor 8, excessive phagocytosis of synapses by astrocytes and microglia could be reduced (Tzioras et al., 2023). Activation of purinergic ligand-gated ion channel 7 receptor is reported to upregulate glycolysis (Di Virgilio et al., 2022), in turn, promoting the clearance of Aβ from astrocytes (Beltran-Lobo et al., 2023). Under neuroinflammatory conditions triggered by Aβ in AD, microglia are primarily stimulated to release interleukin-1beta and tumor necrosis factor-α that affect astrocytes. Thus, Aβ can indirectly stimulate type A1 astrocytes through activated microglia, which is associated with upregulation of glycolysis in type A1 astrocytes. In addition, the connecting proteins of astrocytes are affected, which, in turn, influences the size of astrocytes and increases the distance between astrocytes and neurons, thus affecting neuronal function (Saab et al., 2013; Abudara et al., 2015; Deng et al., 2023). Eventually, both astrocytes and microglia are activated, which concomitantly exacerbate phagocytic synapses, impair the blood–brain barrier, and ultimately induce neuronal damage (Morita et al., 2019; Jackson et al., 2022).

Diminished glycolysis in oligodendrocytes in Alzheimer’s disease

Oligodendrocytes encircle the exterior of axons to maintain and protect the myelin sheath, regulate the integrity and permeability of the blood–brain barrier, and facilitate energy metabolism by transporting metabolic substrates of glycolysis into axons via protein channels located in myelin sheaths (Saab et al., 2013; Cheng et al., 2021). Glycolysis is the primary metabolic pathway of oligodendrocytes that generates substantial amounts of pyruvate and lactate. Oligodendrocytes are the fastest lactate-consuming cell type in the brain (Rinholm et al., 2011). These metabolic substrates enter the axon via MCT2 on the surface and subsequently reach the mitochondria to induce oxidative phosphorylation and production of ATP for maintaining long-term integrity of the axon. Furthermore, oligodendrocytes express MCTs. Lactate and pyruvate are delivered to the axon space via the oligodendrocyte-specific monocarboxylate transporter MCT1 (Ramya et al., 2023), followed by uptake by neurons through MCT2 to provide energy (Fünfschilling et al., 2012; Zhou et al., 2018; Pan et al., 2022; Figure 5).

Figure 5.

Glycolysis between oligodendrocytes and neurons in Alzheimer’s disease.

Oligodendrocytes consume substantial amounts of glucose and lactate to meet the energy requirements of axons. These cells express MCTs, which are specific for glucose-derived metabolites, and lactate and pyruvate are transported into the axon space of neurons via MCT1. The metabolic substrates enter the axon via MCT2, followed by transport into mitochondria, producing adenosine triphosphate (ATP) to maintain the energy requirements of the axon. In Alzheimer’s disease, oligodendrocytes exhibit diminished glycolysis and reduced ability to take up glucose, leading to axonal energy deficiency that potentially contributes to neuronal dysfunction and loss. Created with BioRender.com. ATP: Adenosine triphosphate; MCT: monocarboxylic acid transporter.

Myelin degeneration and white matter loss due to oligodendrocyte death are early pathological changes in AD. The glycolytic metabolic pathway of oligodendrocytes is disrupted under neurodegenerative conditions (Saito et al., 2021) and expression of glycolytic genes, including PFK, phosphoglycerate mutase, and pyruvate kinase M, is extensively impaired (Fu et al., 2014; Saito et al., 2021). A recent study confirmed that hyperactivation of dynamin-related protein 1 in mature oligodendrocytes induces glycolytic deficits in the AD model via hexokinase 1 (Xiang et al., 2021). Thus, dysfunction of glycolysis in mature oligodendrocytes exacerbates the developmental process of AD through activating NOD-, LRR- and pyrin domain-containing protein 3 inflammatory vesicles, leading to pyroptotic injury, demyelination, and white matter degeneration (Zhang et al., 2020b). Since sirtuin 2 is enriched in oligodendrocytes and undetectable in neurons, oligodendrocytes support axonal energy metabolism via transcellular transmission of sirtuin 2 (Chamberlain et al., 2021). Overall, glucose metabolism is significantly disrupted in AD.

Influence of oligodendrocytes with altered glycolysis in exacerbate on other cells

Oligodendrocytes that utilize glycolysis as the primary metabolic pathway not only support myelin formation in neurons but also produce a series of growth factors that regulate neuronal survival, including brain-derived neurotrophic factor, neuromodulin-1 (Ding et al., 2021), and neurotrophic factor-3 (Cong et al., 2020). Metabolic coupling of oligodendrocytes and axons is associated with extracellular K⁺ (Looser et al., 2024). Oligodendrocytes produce lactate as a major energy fuel for neurons and are more tightly linked with axons through the myelin sheath than astrocytes, providing for the metabolic demands for neurons primarily through the glycolysis pathway (Philips and Rothstein, 2017). Activation of oligodendrocyte NMDA receptors stimulates GLUT1 expression, leading to elevated glucose uptake, enhanced glycolysis, and increased lactate levels, which results in the formation of myelin sheaths that support axons (Saab et al., 2016). Due to the complex structure of neurons, ATP molecules produced in the cytosol cannot be transported via diffusion into the long axon. Therefore, metabolic substrates produced in oligodendrocytes enter the axon via MCT2 on the surface, which are then transported into mitochondria and undergo oxidative phosphorylation for production of ATP. Moreover, axonal energy expenditure accounts for half of the energy consumed by the entire neuron to maintain neurotransmitter cycling and release. Owing to the lack of lactate dehydrogenase, glycolysis in mature oligodendrocytes mainly produces pyruvate, while lactate is predominantly generated during myelin regeneration and development and delivered to neurons to energize axons (Späte et al., 2024). Lactate supplied to neurons by oligodendrocytes is essential for the maintenance of their function. Therefore, metabolic dysfunction in oligodendrocytes is a key contributor to the development of disorders associated with axonal energy deficiency and neurodegeneration (Gil and Gama, 2023; Li and Sheng, 2023; Figure 5).

Downregulation of glycolysis-related genes in oligodendrocytes in AD brain was recently demonstrated via RNA sequencing (RNA-Seq) (Saito et al., 2021). Under AD conditions, axonal swelling due to impairment of myelin function promotes deposition of Aβ. Owing to the reduced glycolysis of oligodendrocytes, sufficient energy for myelin regeneration is not produced, leading to destruction of axons, thereby impairing the function of neurons and exacerbating AD pathology (Depp et al., 2023; Wood, 2023). Moreover, during neuroinflammation, enhanced glycolysis of microglia inhibits the mitochondrial function of oligodendrocytes through production of nitric oxide and itaconic acid, which is not conducive to the formation of myelin (Suhail et al., 2023). Transport of lactate is also affected, preventing neurons from receiving sufficient energy. Mitochondrial and axonal functions are further affected by pro-inflammatory factors, causing disruption of homeostasis within the brain. Single-cell sequencing revealed the same transcriptional response to Tau in oligodendrocytes and astrocytes of AD brain. Furthermore, alterations in the key glycolytic enzyme HK2 correlated with TREM2-related phagocytosis in microglia and single-cell sequencing revealed that loss of TREM2 had little effect on oligodendrocytes and astrocytes (Lee et al., 2021b). In summary, both oligodendrocytes and astrocytes are metabolically coupled to neurons to maintain normal neuronal activity or restore their energy deficit (Rosko et al., 2019).

Limitations

The studies included in this review have a number of limitations that should be taken into consideration. The alterations in glycolysis in neurons, microglia, astrocytes, and oligodendrocytes in AD brain as well as glycolysis crosstalk between neurons and other cell types have been discussed in detail. Although investigation of glycolysis has contributed to our understanding of the diagnosis of AD and uncovered novel therapeutic avenues, the specific key molecules of this pathway in different cells related to AD have not been summarized fully identified due to current research limitations. Consequently, clear targets for effective diagnosis and treatment of AD remain to determined. Further in-depth studies from the perspective of glycolysis are essential to identify novel biomarkers for AD.

Conclusion

AD is a chronic, progressive, and neuronal degenerative disease for which accurate diagnosis and effective treatment options are yet to established. Aβ and phosphorylated Tau in plasma serve as key biomarkers of AD. In recent years, positron emission tomography Aβ and Tau biomarkers have been used for diagnosis of AD. However, plasma biomarkers and clinical imaging can only distinguish specific stages of AD and are not effective at the earlier stages. The available diagnostic methods have limited sensitivity and specificity. Furthermore, positron emission tomography-Aβ and Tau are expensive modes of treatment for the majority of AD patients. The identification of reliable and accurate biomarkers therefore remains a critical unmet need (Hergesheimer et al., 2019; Saito et al., 2021).

The majority of studies highlight that main glucose metabolism pathway switches to glycolysis in AD driven by Aβ and phosphorylated Tau. Decreased glycolysis has been shown to be correlated with severity of Aβ and tau pathology (Zhang et al., 2021). The distribution of glycolytic metabolism in brain regions is linked to Aβ, whereby elevated glycolysis metabolism is associated with larger amounts of Aβ in brain regions. A higher degree of abnormal tau phosphorylation is associated with lower glycolysis rates (Vlassenko et al., 2010, 2018). In addition, activated astrocytes in AD alter their immune and metabolic functions, with increased glycolytic ATP production and a lack of cytokine secretion in response to Aβ, thereby contributing to AD pathology (Fleeman et al., 2023). Different stages of AD exhibit varying degrees of Aβ and Tau phosphorylation, ultimately leading to distinct glycolytic changes. Therefore, alterations in molecules in the glycolytic pathway may serve as biomarkers of AD. During neurodegenerative disease, glycolysis is variably modified in different cells, and therefore, a direct search of glycolysis metabolites is not a reliable method for diagnosis of AD. Single-cell sequencing can effectively be utilized to identify the changes in glycolytic gene types in different cell types and combined with spatial transcriptomes to further analyze changes in glycolytic genes and enzymes for identification of those closely related to the onset and different stages of AD as well as the corresponding related molecules in plasma. Accordingly, glycolytic enzymes that are modified in plasma can be detected and utilized for improving diagnosis of AD.

Since the glycolysis pathways in different cells tissues from AD brain tissue vary, the effects are also diverse (Figure 6). For example, in AD, glycolysis is enhanced in neurons and microglia, but decreased in astrocytes and oligodendrocytes. Therefore, while it is difficult to consider glycolysis as a therapeutic target for AD, corresponding measures may be implemented by targeting different cellular glycolytic changes, such as augmenting glycolysis in oligodendrocytes, gene editing, or interfering with specific glycolytic enzymes, which may induce alterations in the activity of oligodendrocyte glycolysis. Consequently, oligodendrocytes can be induced to supply energy to neuronal axons, maintain myelin and axon homeostasis, and improve cognitive impairment. Targeting these pathways may alter astrocyte glycolysis activity, thereby promoting the astrocyte–neuron energy supply and reducing the inflammatory response caused by toxic astrocytes, ultimately improving cognitive capacity. Inhibition of glycolysis in microglia, such as through suppression of the key glycolytic enzyme HK2 specifically expressed in these cells, can reduce the activation and inflammatory response of microglia, promote their fat metabolism, improve phagocytic function, reduce pathological changes, and improve cognition (Leng et al., 2022).

Figure 6.

Glycolytic links among neuronal cells in Alzheimer’s disease.

In Alzheimer’s disease, the effects of altered glycolysis in individual cells on neurons are as follows: downregulation of glycolysis in astrocytes reduces the production and secretion of transmitters as well as supply of lactate to neurons, while upregulation of glycolysis in microglia decreases phagocytosis of amyloid-β and promotes excessive pruning of synapses, resulting in neuronal loss and dysfunction. Downregulation of glycolysis in oligodendrocytes decreases energy delivery to neuronal axons, promoting neuronal dysfunction, reduced synaptic connectivity, and impaired information transmission. Downregulation of glycolysis in oligodendrocytes decreases energy delivery to neuronal axons, causing axonal dysfunction, reduced synaptic connectivity, and impaired neuronal signaling. Created with BioRender.com.

In conclusion, the glycolysis pathway represents a promising target for the diagnosis and treatment of AD. However, the related molecular mechanisms and changes in glycolysis-related enzymes in different stages and cell types of AD require further research to identify useful biomarkers and therapeutic targets that can be utilized to achieve effective diagnosis and treatment.

Funding Statement

Funding: This work was supported by the National Natural Science Foundation of China, No. 82271214 (to ZY) and the Natural Science Foundation of Hubei Province of China, No. 2022CFB109 (to ZY).

Data availability statement:

Not applicable.