Glucose is the only source of energy in the brain. When the utilization of glucose in the brain is impaired, the function of brain will be affected to a large extent (Vercruysse et al., 2018). In a healthy brain, glucose metabolism is an important source of energy for neurons. And when glucose utilization in the brain decreases, so does human cognitive ability (Tingley et al., 2021). In total, 30% of glucose used by the human brain is aerobic glycolysis (Magistretti and Allaman, 2015). Astrocytes are the most abundant cell type and major consumer of glucose in the central nervous system (CNS). Glycolysis and lactate production are metabolic features of astrocytes, while neurons meet their energy requirements mainly through oxidative phosphorylation (Bélanger et al., 2011; Magistretti and Allaman, 2015). Aerobic glycolysis of astrocytes provides important nutritional support for CNS neurons. It has been shown that SNX27^R196W (equivalent to human R198W) attenuates glucose uptake by astrocytes via Glucose Transporter 1 (GLUT) in mice, and causes a decrease in lactate production and deficits in synaptic function and learning behavior (Zhang et al., 2022).

NSCs in the SVZ and SGZ regions undergo various stages in the process of differentiation into mature neurons. In this process, stem cells rely on glycolytic metabolism rather than mitochondrial oxidative phosphorylation (Folmes et al., 2011). Mitochondria manage metabolites and the epigenetic state of NSCs, regulating the differentiation process of NSCs during AHN (Khacho et al., 2019). In AD, excessive aggregation of Aβ in the brain induces mitochondrial dysfunction in neural progenitor cells and inhibits the differentiation of newborn neurons by reducing glucose utilization, leading to AHN dysregulation (Kim et al., 2022). In addition, abnormal insulin metabolism is another essential feature of AD, and insulin resistance mainly affects glucose metabolism of the brain in the hippocampus (Watson and Craft, 2003). The reduction of glucose transport and uptake may be caused by GLUT deficiencies. The GLUTs distributed in the brain are mainly GLUT1 and GLUT3, with GLUT1 involved in glucose transport to brain glial cells and GLUT3 transporting glucose to neurons. It has been demonstrated that metformin can normalize glucose transport and uptake in the brain by inhibiting the activity of GSK-3β and increasing the expression of GLUT1 and GLUT3 to promote neuronal regeneration and prevent neuronal damage (Pilipenko et al., 2020).

In addition to important substrates of energy metabolism such as glucose and ketone bodies that provide energy to the brain, lactate metabolism also plays a crucial role in memory. Under high energy demand, lactate is involved in regulating neurogenesis-related processes such as angiogenesis, neuronal excitability and plasticity. Moreover, lactate is also involved in regulating the metabolism and signaling pathways of non-neural cells in the neurogenic microenvironment, such as endothelial cells, oligodendrocytes, microglia and astrocytes (Matsui et al., 2017; Lev-Vachnish et al., 2019). Among the large number of metabolites consumed by oligodendrocytes, in addition to glucose, there is also important lactate, which is used for myelin formation or myelin repair after demyelination injury to promote axonal integrity. Furthermore, the addition of lactate under low glucose conditions can rescue oligodendrocyte lineage cells and promote their myelin formation. It has been suggested that oligodendrocyte dysfunction and early demyelination in APP/PS1 mice may accelerate the progression of AD disease (Ichihara et al., 2017). And lactate treatment produces more myelin compared to glucose, suggesting that oligodendrocytes may be more dependent on lactate as a substrate for myelin production (Rinholm et al., 2011). Some studies have shown that when demyelinating lesions occur in mice, the expression of p-CREB and BDNF will be significantly reduced, further affecting the development of mature neurons in mice, and damaging AHN (Hahn et al., 2022).

Lactate metabolism in the CNS is categorically inseparable from the process of exploring lactate transport, and there are 1–14 isoforms of Monocarboxylate Transporter (MCT), which are distributed in different cells and play different roles. In the central nervous system, MCT1, MCT2, and MCT4 facilitate lactate transport between nerve cells (Pierre et al., 2000). Lactate transport is required for memory formation and synaptic transmission in the hippocampus. When MCT transport is dysfunctional, it may lead to impaired lactate transport, which in turn hinders energy metabolism and causes memory impairment (Nagase et al., 2014). In endothelial cells, the PI3K/AKT pathway regulates MCT-1 expression and subsequent lactate transport, and the transported lactate activates HCAR1 on astrocytes to regulate vascular endothelial growth factor (VEGF) levels, thereby enhancing angiogenesis and promoting AHN. Thus, abnormal lactate accumulation in the hippocampus disrupts AHN and impairs learning and memory functions (Scandella and Knobloch, 2019). According to the astrocyte-neuron lactate shuttle hypothesis, astrocytes promote glucose consumption or glycogen breakdown to enhance lactate production, which is then transported to neurons via MCT to support neuronal activity. In AD, the astrocyte’s ability to take up glucose is diminished and lactate production is reduced, which affects the subsequent neuronal regeneration process (Nicola and Okun, 2021). In the course of neuroinflammation, MCT1 dysfunction and changes in lactate levels affect the pro-inflammatory response of microglia. Microglia can phagocytose and remove apoptotic cells, including neoplastic neurons through phagocytosis to further balance the proliferation and survival of neoplastic neurons (Kong L. et al., 2019).

A growing body of research suggests that voluntary physical exercise can upregulate specific neurotransmitters levels in the brain, including the brain-derived neurotrophic factors (BDNF) and VEGF, and increase adult hippocampal neurogenesis, in which lactate plays an important role (Vivar and van Praag, 2017). During physical exercise, lactate concentration in the blood increases, which facilitates neuronal differentiation and survival of newborn neurons (Lev-Vachnish et al., 2019). But how this relationship develops in AD requires further research.

Extracellular aggregation of neuritic plaques and intracellular aggregation of neurofibrillary tangles are histopathological hallmarks of AD and are closely associated with synaptic defects and neurodegeneration (Yamaguchi et al., 1991). Amyloid Precursor Protein (APP) is sheared by β-secretase and γ-secretase to form Aβ fragments, which form neuritic plaques in the brains of AD patients. Both β-secretase and γ-secretase are intact lipoproteins, and their action depends mainly on the level of lipids present in the membrane (Campos-Peña et al., 2022). Evidence suggests that AHN disorders caused by lipid metabolism disorders make patients more susceptible to AD. Monoacylglycerol lipase (Mgll), a hydrolase that breaks down endogenous fats, is now considered a potential target for AD. It was demonstrated that in postmortem AD patients and 3xTgAD mouse models, there is an age-dependent induction of Mgll due to diminished aPKC-CBP signaling, thereby reducing neuronal production in the brains of AD patients and impairing their cognitive function (Syal et al., 2020).

It is well known that cholesterol is the main protein required to maintain the dynamic homeostasis of cell membranes, and the brain is the organ with the highest cholesterol content. It has been demonstrated that cholesterol homeostasis affects the production of amyloid protein. In addition, there are many lipids present in the cell membrane, such as sphingomyelin and cardiolipin, which may alter the function of a variety of transmembrane proteins (Fabiani and Antollini, 2019). In the adult brain, 70–80% of cholesterol is found mainly in the myelin sheath, with the rest in the plasma membrane of astrocytes and neurons, protecting their morphologies and synaptic transmission processes (Dietschy and Turley, 2004; Zhang and Liu, 2015). High levels of cholesterol in the cell membrane also cause significant changes in the dynamic homeostasis of neurons, which affects the proteolytic activity of γ-secretase (a transmembrane protein), including promoting amyloidogenesis, increasing APP processing, producing amyloid, and affecting the microenvironment of AHN (Kao et al., 2020). ApoE is a glycoprotein mainly secreted by astrocytes, which is involved in regulating lipid transport, synaptogenesis and amyloid clearance, and also plays an important role in hippocampal neurogenesis. There are three common isoforms of ApoE in humans, including ApoE2, ApoE3, and ApoE4. The study indicated that overexpression of ApoE4 decreased adult neurogenesis in mice comparing with wild-type controls, while ApoE3 and ApoE2 expression promoted the proliferation and genesis of neural progenitor cells in the DG region (Koutseff et al., 2014). Moreover, ApoE4 can negatively affect adult hippocampal neurogenesis by modulating γ-aminobutyric acid interneurons and decreasing levels of neurosteroids (e.g., allopregnanolone). In contrast, ApoE3 can counteract chemokine-induced neuroinflammation and improve AHN (Suidan and Ramaswamy, 2019). Therefore, ApoE is expected to be a therapeutic target for AD (Chen et al., 2021).

In addition, by studying the “senile plaques” in the brain of AD patients, it was found that in addition to Aβ aggregation, there are many kinds of lipids in the senile plaques, such as ganglioside. Specific accumulation of monosialic acid gangliosides was found in the hippocampal subgranular region of a 12-month-old 5xFAD-AD mouse model, suggesting a potential relationship between the accumulation of plaque-associated gangliosides and damaged neural regeneration (Kaya et al., 2020).

DNA methylation is an epigenetic mechanism that occurs by the covalent transfer of a methyl group to the C-5 position of the nuclear base cytosine to form 5-methylcytosine, which is involved in the regulation of gene expression (Moore et al., 2013). In order to investigate whether epigenetic alterations lead to late-onset AD, some researches focused on the DNA methylation status of the risk genes. The results showed that there is a decrease in CpG methylation at the APP gene promoter in neurons and glial cells, accompanied by an increase in APP gene expression, which in turn leads to an overproduction of Aβ (Tohgi et al., 1999). In addition, changes in DNA methylation also occur in other related genes, such as MCF2L, MAP2, ANK1, HOX3A, etc. (Gasparoni et al., 2018).

Among the pathological features of AD, impairments in epigenetic mechanisms also lead to the generation of damaged neurons by neural stem cells, which will aggravate the loss of neurons and the defects of learning and memory (Li et al., 2016). DNA methylation of promoters can result in transcriptional repression through DNA methyltransferases (DNMTs) in neurodevelopment, while the deletion of DNMT1 in neural progenitors impairs the maturation and survival state of neurons, causing precocious astrocyte differentiation (Hutnick et al., 2009). And it was shown that the IL-6/JAK2/STAT3 pathway can regulate neurogenesis by improving DNMT1 in NSCs, promote DNA demethylation to regulate NSCs status at the epigenetic level, and further regulate AHN (Kong X. et al., 2019; Figure 2). The development of neural progenitor cells is an important node in the process of AHN, and mitochondria in neural progenitor cells play a crucial role in AHN (Gage, 2019). Whether in AD model mice or in Aβ-induced in vitro cell lines, the aggregation of Aβ can induce mitochondrial damage in neural progenitor cells and lead to the defect of AHN and cognitive function. In-depth mechanistic studies revealed that damage to mitochondria causes degradation of lysine demethylase 5A (KDM5A) in neural progenitor cells, which in turn result in AHN deficits. It may be because the genetic reduction of KDM5A expression reduces the transcription of BDNF in the brain, inhibits neural differentiation and leads to memory deficits (Bath et al., 2012; Kim et al., 2022). Additionally, the human neural progenitor cells induced from pluripotent stem cells were used to establish a simple in vitro adult neurogenesis model to study DNA methylation in the context of AD disease. And it found that the methylation levels of NXN genes were elevated and differential DNA methylation were observed in immature neurons by quantifying genes related to neurogenesis in the hippocampal region in the context of simulated AD (Blanco-Luquin et al., 2022).

The appearance of neurofibrillary tangles and the aggregation of neural plaques in AD patients are some markers of abnormal histone post-translational modifications during the development of AD, and these abnormal modifications are closely related to the cognitive impairment of AD patients in the later stage. Histones are structural proteins that form DNA nucleosomes. Their N-terminal sequences protrude beyond the boundaries of nucleosomes and provide a surface for the recognition and subsequent interaction of proteins that regulate transcription. They usually participate in the expression and repression of target genes through chromatin modification. At present, histone modifications that have been studied extensively include acetylation, methylation and phosphorylation (Voigt and Reinberg, 2013; Audia and Campbell, 2016). Phosphorylation is one of the most common modifications in proteome biology, and approximately 30% of proteins undergo this modification by adding phosphate groups to serine, tyrosine and threonine residues. There is also growing evidence that phosphorylation modifications in many diseases alter the basic function of proteins and drive cell death signals (Humphrey et al., 2015). Tau protein, a microtubule-associated protein, has been proved to promote the formation of neurogenic fiber tangles by hyperphosphorylation in the brains of AD patients. The phosphorylated Tau protein accumulates excessively in GABAergic interneurons in the DG region of AD patients and mice, which impair the AHN by suppressing GABAergic transmission (Zheng et al., 2020). And this hyperphosphorylated Tau protein accumulation occurs mainly in the early and middle stages of AD. In the late stage of AD, the phosphorylated Tau protein gradually disappears from the nuclei of the granule cell of the DG region (Gil et al., 2022). Heme oxygenase was found to be neuroprotective in AD mice by modulating the levels of p–Ser9-GSKβ and p–Tyr216-GSKβ to improve the survival and proliferation capacity of NSCs and promote AHN in AD disease model (Si et al., 2020). In a mouse model of fragile X-chromosome syndrome, scientists found that neurogenesis could be improved by improving the level of histone acetylation modification to rescue cognitive deficits in mice (Li et al., 2018). In addition, H3K9me3, the ninth lysine on histone H3 is methylated and is a common inhibitory histone modification. Scientists have demonstrated that the expression and distribution of H3K9me3 changes dynamically in dentate gyrus of adult mouse and cultured adult hippocampal neurons, exhibiting high levels of expression early in neurogenesis. And silencing of H3K9 transferase mediated by retrovirus significantly impairs neural progenitor cell differentiation (Guerra et al., 2021). To understand the specific role of histone modifications in AD, more future studies are needed to be carried out.

MiRNAs are a class of single stranded non-coding RNAs with about 19–23 nucleotides, which are important epigenetic and post-transcriptional regulators of mRNA complexity. Due to their small molecular weight, amphiphilic and high solubility, they have strong mobility and are ubiquitous in the central nervous system. They are the minimum information of nucleic acid signal molecules in eukaryotes described so far (Zhao et al., 2020). In recent years, a growing number of studies have shown that miRNAs play a key role in the development of many neurodegenerative diseases, and their role in the pathogenesis of AD involves the regulation of amyloid precursor protein (APP), BACE1, neuronal apoptosis and other factors (Deng et al., 2014). With the development of scientific technology, miRNA dysregulation has also been found to be associated with the development of AD (Rahman et al., 2020). The network analysis of brain miRNAs in AD patients at Braak stage III revealed that a large number of miRNAs were related with the immune system, cell cycle, gene expression, cellular stress response, nerve growth factor signal, Wnt signal and cellular senescence, such as miR-107, 26b, 30e, 34a, 485, 200c, 210, 146a, 34c, 125a. Among them, miR-200c, 146a, 34c, 125 expression is increased in the brains of AD patients, while miR-210, 485, 107 expression is decreased, and the remaining ones are dynamically changed with disease progression (Swarbrick et al., 2019).

As increasing studies have observed the dysregulation of microRNA expressions in AD, more researches have been conducted on their effect on AHN. MiR-9 is one of the most abundant microRNAs in mammalian central nervous system. It can promote neural differentiation of NSCs by targeting related genes to induce neurogenesis (Landgraf et al., 2007; Yoo et al., 2009). And it can inhibit Notch signal pathway (participating in the regulation of nervous system development and stem cell biological activity) in AD and promote NSCs to differentiate into neurons, thus promoting AHN (Li et al., 2017). The expression levels of miR-206 were increased in Tg2576 AD mice and AD patients. Inhibition of miR-206 expression in AD mice could improve Aβ deposition as well as BDNF expression levels, enhance hippocampal synaptic density and neurogenesis, and further improve memory function (Lee et al., 2012). MiR-351-5p is a pathogenic factor of hippocampal neural progenitor cells, which is widely expressed in AD patients. Inhibition of its downstream gene Miro 2 can induce a large number of mitochondrial divisions and lead to bad mitosis, which result in the loss of a large number of normal mitochondria and the death of hippocampal neural progenitor cells (Woo et al., 2020). MiR-132 is one of the consistently downregulated microRNAs in the development of AD. And it is an effective regulator of AHN. When miR-132 levels were restored in the hippocampus, the hippocampal AHN and associated memory deficits can be improved in AD mice (Walgrave et al., 2021). MiR-188-5p expression is also reduced in AD samples, while increasing its expression levels in primary hippocampal neurons and 5xFAD mouse neurons was found to further improve cognitive deficits by improving neuronal survival (Lee et al., 2016).