Serving as the resident macrophages of the CNS, microglia maintain CNS homeostasis; they are also implicated in AD pathology [25, 45]. Upon exposure to pathogenic or damage signals, microglia rapidly activate to acquire different phenotypes exerting either neuroprotection or neurotoxicity [46]. As brain resident innate immune cells - microglia - sculpt neural circuitry and coordinate copious and numerous neurodevelopmental requirements [47].

Microglia, acting as effector cells in the brain’s innate immune system, exhibit an adaptability to perform various specialized functions in AD, including phagocytosis and elimination of harmful clusters of A$\beta$ and tau proteins that contribute to neurodegeneration. These immunological processes necessitate substantial energy resources, which are controlled by mitochondria. Furthermore, microglia exhibit metabolic flexibility, capable of utilizing both glycolysis and oxidative phosphorylation and reprogram their mitochondrial function to meet their energy needs when activated by inflammation [28]. Myeloid Triggering receptor expressed on myeloid cells 2 (TREM2) is a regulatory factor that adapts to mitochondrial metabolism and is only expressed in microglia. Recent studies have shown that TREM2 is involved in multiple microglial activities, including calcium mobilization, phagocytosis, cytokine production, energy metabolism and immune response regulation. TREM2 is highly expressed in the brains of AD patients. Modulation of TREM2-mechanistic target of rapamycin (mTOR) signaling increases microglial phagocytosis in AD [48]. Increasing evidence suggests that TREM2 maybe involved in regulating microglial polarization of the anti-inflammatory Macrophages (M$\mathrm{\Phi }$s) type 2 (M2) phenotype through multiple signaling pathways, including the Toll-like receptor 4 (TLR4)-mediated pathway, Phosphatidlinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. In the field of neurodegenerative diseases, TREM2 has been observed to reduce the accumulation of lactate dehydrogenase (LD) in aging microglia. At the same time, studies have shown that TREM2 restores microglia homeostasis through the TREM2-Apolipoprotein E (APOE)-mediated pathway, possibly by regulating key transcription factors such as transforming growth factor $\beta$ (TGF-$\beta$) that are homologous to microglia [49]. APOE is a glycoprotein involved in the regulation of lipid metabolism and is widely expressed in astrocytes, microglia, vascular parietal cells and choroid plexus cells in the central nervous system [50]. APOE is a polymorphic gene with three common alleles: $ϵ$2, $ϵ$3, and $ϵ$4. Although the most common allele, APOE $ϵ$3 (APOE3), is not associated with the disease, APOE $ϵ$4 (APOE4) is the largest known genetic risk factor for late-onset AD. APOE4 is involved in AD pathogenesis by affecting microglial reactivity, synaptic integrity and plasticity, lipid transport, cerebrovascular integrity and function, and glucose metabolism, some of which are independent of A$\beta$-associated pathways [51]. Under pathological conditions and injury, APOE is found to be sharply upregulated in activated microglia and stressed neurons. Investigators have found that the TREM2-APOE pathway plays a key role in microglial phenotypic change from a homeostatic to a neurodegenerative phenotype.

Microglia express glycolysis and oxidation and in the absence of glucose, they are metabolically flexible and have the capacity to quickly adapt to consume glutamine as an alternative metabolic fuel. Glutamine hydrolysis supports the maintenance of motor and damage sensing functions of microglia processes in insulin-induced hypoglycemia in blood glucose or in vivo in acute brain sections. This metabolic adaptation sustains mitochondrial function and is regulated through mTOR-dependent signaling. This plasticity allows microglia to maintain their critical monitoring and phagocytosis roles even after disruption of neural energy homeostasis [52, 53]. Glucose deprivation may sensitize microglia to release inflammatory mediators and major microglia functions in survival and inflammation, which probably result in psychiatric comorbidities of ischemia, diabetes, and/or metabolic disorders [54]. Microglia also undergo a transition from a resting phenotype to a reactive phenotype, known as disease-associated microglia. There is a common misconception that M1, the glycolytic type, and M2 are dependent on the oxidative phosphorylation phenotype. The glucose uptake of microglia is mainly promoted by glucose transporter type 1 (GLUT1), especially within inflammatory environments [55].

Microglia continuously monitor the brain parenchyma to detect changes in neuronal activity and homeostatic processes to maintain normal brain function. Metabolic pathways participating in microglial activity adapt and promote cell phenotypes. While mitochondrial oxidative phosphorylation is efficient in the production of ATP, microglia produce ATP faster and produce intermediates for cytokine production and cell growth. In macrophages, pro-inflammatory stimulation induces a metabolic transition from oxidative phosphorylation to glycolysis, a phenomenon similar to the Warburg effect in tumor cells. Alterations in metabolic function allow macrophages to respond appropriately to changing environments and much evidence suggests that, similar to macrophages, microglia are able to variably adapt to the energy matrix. Neuroinflammation frequently manifests in various neurodegenerative disorders and metabolic reprogramming of microglia has been found in neurodegenerative diseases [56].

Mitochondria serve as the primary energy-generating organelles in human cells. The genetic blueprint for mitochondria, mitochondrial DNA (mtDNA) is a circular, double-stranded molecule comprising 16,569 nucleotides. It encodes 13 messenger RNAs, 2 ribosomal RNAs and 22 transfer RNAs [57].

Proteins transcribed from mitochondrial messenger RNAs form essential subunits of the oxidative phosphorylation complexes I to V except complex II. These complexes play a key role in mitochondrial oxidative phosphorylation, influencing electron transfer and ATP generation [58, 59]. The principal sites for oxidative phosphorylation and ATP generation are mitochondria, mitochondria supply about 95% of the energy needed for cellular functions [60]. Under hypoxic conditions, cells rely solely on glycolysis for ATP production, which leads to the conversion of pyruvate into lactic acid. In aerobic conditions, glycolysis produces pyruvate that enters the tricarboxylic acid (TCA) cycle, also known as the citric acid or Krebs cycle, facilitating mitochondrial ATP synthesis [61].

Mitochondria generate circulating metabolites from the TCA cycle that influence cellular fate and function. TCA cycle metabolites have traditionally been regarded as by-products of cellular metabolism. These metabolites are crucial for the biosynthesis of macromolecules, including nucleotides, proteins and lipids. While fundamental to cellular homeostasis, these processes occur rapidly. It has been recognized that metabolites in the TCA cycle are also involved in controlling chromatin modification, DNA methylation and change of function post-translational protein modification [62].

Mitochondrial morphology exhibits significant variations across different cell types and tissues and swiftly responds to external stimuli and metabolic signals such as nutritional status. The structure of mitochondria, characterized by continuous fission and fusion of their inner and outer membranes, has been intensively studied for its functional implications. Unregulated fission leads to mitochondrial disruption, commonly linked with metabolic dysfunction and disease. Controlled fusion produces stable mitochondrial networks, which counteract metabolic damage, maintain cellular integrity, and inhibit autophagy [63]. Mitochondrial morphology undergoes constant alterations through a dynamic interplay of fusion, fission and cytoskeletal trafficking. The balance between fission and fusion rates determines both the extent to which mitochondria form closed networks and their length. Moreover, these rates are controlled by mitochondrial metabolism, harmful conditions and their cellular environment. Fusion and fission are significant for mitochondrial redistribution, growth, and maintaining a robust mitochondrial network. Moreover, fission and fusion process of mitochondria exert a significant role in disease-associated procedures, including mitochondrial apoptosis and autophagy.

Three members of the Dynamin family play an important role in fission and fusion mechanisms [64]. As dynamic organelles, mitochondria can fuse and divide. These continuous and simultaneous processes are mediated by nuclear DNA-coding proteins, which act upon the mitochondrial membrane. The balance of fission and fusion dictates mitochondrial morphology, adapting to the metabolic demands of the cell. Additionally, these two processes are essential for optimizing mitochondrial bioenergetic and functional capabilities [65]. Maintaining a healthy network of interconnected mitochondria is crucial for ensuring the proper positioning of mitochondria towards high-energy-demanding neurons, as well as safeguarding neurons by minimizing oxidative stress. To achieve these objectives, it is imperative to achieve an equilibrium between mitochondrial fusion and fission processes [66].

Implications can be observed in conditions like AD and cerebral ischemia/reperfusion, where microglial mtDNA undergoes mutations or deletions [67, 68]. Recent research has reported a correlation between levels of microglial mtDNA deletions in distinct brain regions with varying pathological susceptibilities to AD and their corresponding disease stages [69]. Once taken up by nearby microglia, mtDNA will binds to cyclic guanosine 5${}^{\prime }$-monophos-phate-adenosine monophosphate (GMP-AMP) synthase (cGAS) protein and activates the cGAS-Sting cytoplasmic DNA recognition pathway, thereby increasing the expression of interferon-beta (IFN-$\beta$) [67]. Additionally, after treated by mtDNA, the human microglia will produce large amounts of ROS, activate the nuclear factor-$\kappa$B (NF-$\kappa$B) signaling pathway, synthesize excessive pro-inflammatory cytokines, aggravate the inflammatory microenvironment and lead to cell death and tissue damage [70]. Therefore, the release of damage-associated molecular patterns is increased and more microglia are activated, triggering a feed-forward cycle of neuroinflammation [71]. These observation suggest that microglial mtDNA abnormalities contribute to glial activation and deposition of pathogenic material deposition in AD.

Accumulating in vitro and in vivo evidence suggests that metabolic impairments in the CNS contribute to both microglial activation and cell death, exacerbating pathology in neurodegenerative diseases [72]. Oxidative stress and reactive oxygen species generation are pivotal mechanisms in this process [72, 73]. Microglia are attacked by oxidative stress, and reactive oxygen species, leading to mitochondrial dysfunction. Microglia with mitochondrial dysfunction increase mitochondrial damage, increase the release of inflammatory factors into the extracellular space and overproduce ROS. These pathological changes further increase the inflammatory response of microglia. Considerable proteomic analyses of AD brains and cerebrospinal fluid have demonstrated elevated levels of proteins linked to glucose metabolism, coinciding with early-stage microglial activation [74]. Upon inflammatory stimulation, microglia shift their metabolic pathway to less efficient glycolysis, potentially undermining their metabolic efficiency and phagocytic capability, ultimately leading to microglial dysfunction and A$\beta$ accumulation [75, 76]. Analogous observations have been reported in murine models [45]. Additionally, it has been observed by the current authors that a spatial correlation exists between aerobic glycolysis in cognitively normal young adults and A$\beta$ deposition in individuals with both dementia of the Alzheimer’s type and cognitively normal participants with elevated A$\beta$ levels [77].

An increasing body of literature highlights the significant role of mitochondrial fusion/fission imbalance in microglia-mediated neuroinflammation in AD. Evidence has demonstrated that activated microglia in AD mouse models exhibit mitochondrial damage due to dysregulated mitochondrial dynamics [78]. In neurodegenerative conditions, neuronal debris is believed to initiate glial-mediated neuroinflammation, contributing to further neuronal loss. Notably, this phenomenon has been specifically observed in microglia. The ratio of damaged to functional mitochondria released from microglia and the resultant neuronal damage, are both regulated by Fis1-mediated mitochondrial fragmentation within these glial cells [79].

Recent studies have suggested that defective mitophagy might play a role in the development of AD. Further research has shown that mitophagy is impaired in the hippocampi of patients with AD, as well as in induced pluripotent stem cell-derived human neurons and animal models of the disease [80].