Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss and cognitive dysfunction (1). The typical pathological changes in AD are neuronal plaques and neurofibrillary tangles (2). Oligomeric amyloid-beta peptide (Aβ) has been shown to play an important role in cognitive impairment in AD. The primary targets of Aβ are synapses and synapse-related signaling pathways, which damage synaptic plasticity, learning and memory (3). Another key component of AD pathogenesis is tau protein hyperphosphorylation to form neurofibrillary tangles (NFTs). NFTs are less susceptible to degradation by proteolytic enzymes and accumulate in neurons, disrupting the normal function of neuronal axons, leading to structural and functional abnormalities of synapses, interfering with synaptic transmission between neurons, and ultimately leading to neurodegeneration (4). Thus, synaptic loss and altered synaptic plasticity are the neurobiological basis of cognitive impairment in Alzheimer’s disease, and synaptic damage is a manifestation of AD pathological impairment.

Synapses are the key sites of functional connections and information transfer between neurons, and synaptic plasticity is the cellular and morphological basis of learning and memory (5, 6). Synaptic plasticity is thought to play key roles in the development of neural circuitry and impairments in synaptic plasticity contribute to several prominent neuropsychiatric disorders, such as AD (7). Synapse clearance, also known as synaptic elimination, can eliminate unnecessary synapses and keep the morphological and functional maturation of the remaining synapses, has been thought to be a critical step in neural circuits stability and an essential mechanism underlying synaptic plasticity in the central nervous system (CNS) (8). Mounting evidence indicates that microglia plays an important role in synapse clearance (9).

Microglia are resident immune cells in the CNS that regulate brain development, maintenance of neuronal networks, and injury repair (10). Microglia serve as brain macrophages. They are responsible for the elimination of protein aggregates, redundant synapses, and other particulate and soluble antigens that may endanger the CNS. Microglia functional changes are implicated in brain development and aging, as well as in neurodegeneration (11). Studies have shown that normal microglia phagocytose and clear toxic Aβ oligomers, preventing the development of AD (12). However, excessive Aβ oligomers can stimulate the complement cascade pathway and induce microglia to excessively phagocytose and clear synapses in a manner similar to normal synaptic pruning, resulting in synaptic loss in AD patients (13). Overall, microglia can mediate synapse loss in AD progression. However, the mechanisms of microglial regulation remain to be investigated.

Triggering receptor expressed on myeloid cells 2 (TREM2) is an AD risk gene identified in recent years, and mutations in its coding region significantly increase the risk of AD (14, 15). TREM2 is mainly expressed by microglia in the nervous system and regulates microglial activation, proliferation, survival, phagocytosis, and other biological functions. Studies have shown that TREM2 is essential for synaptic clearance (16), but the specific mechanism by which TREM2 regulates synaptic clearance still needs to be explored.

Apolipoprotein E (APOE), the strongest genetic risk factor for AD, regulates neurodegeneration mainly by modulating microglial activation (17). APOE is synthesized and secreted mainly by astrocytes in the activated state, but in AD, the level of APOE expression in plaque-associated microglia is significantly increased and strongly induced in a TREM2-dependent manner (17, 18). Emerging evidence suggests that APOE binds to TREM2 and APOE are putative ligands for TREM2 (19), thus raising the possibility of an APOE-TREM2 interaction may drive the transcriptional phenotype of dysfunctional microglia and modulate AD pathology (20). However, whether APOE-TREM2 pathway participate in microglia-induced synaptic clearance needs further investigation.

Recent findings suggest that the classic complement cascade mediates CNS synaptic clearance (21, 22). The complement proteins C1q and C3 are involved in synaptic clearance by microglia (23). During central nervous system development, redundant neuronal synapses express the complement protein C1q, which is the initiator protein of the classic complement cascade and activates CR3 receptors, and microglia are the only cells in the brain that can express CR3 receptors (24). Activation of the complement signaling pathway allows microglia to recognize synapses, leading to synaptic clearance (25). Inhibition of C1q, C3 or the microglial complement receptor CR3 reduces microglial phagocytosis and prevent synaptic loss (26).

In this review, we systematically summarized the possible mechanisms of microglia involved in synaptic clearance in AD, comprehensively reviewed the role of TREM2 in microglia regulating synaptic clearance and explore the relationship of TREM2, APOE and C1q in synaptic clearance of microglia. We proposed our hypothesis that TREM2 interacts with APOE and C1q to promote synaptic clearance and impaired synaptic plasticity in AD. This review provides new insights into the role of TREM2 regulation in microglia synaptic clearance and provides potential prospects for the treatment of AD.

In recent years, genome-wide association studies (GWAS) have identified more than 25 genetic loci that are strongly associated with the risk of developing late-onset Alzheimer’s disease (LOAD), one of them is TREM2 gene variants (44). TREM2 has been suggested to play a crucial role in AD pathogenesis. TREM2 may act as a multifaceted player in microglial functions in AD brain homeostasis. TREM2 can not only influence microglial functions in amyloid and taupathologies, but also participate in inflammatory responses and metabolism. In this review, we will focus the role of TREM2 in microglia-mediated synaptic clearance in AD.

APOE is also undoubtedly associated with LOAD (45). AD patients carrying the ϵ4 allele of APOE have an earlier age of onset, more severe amyloid, tau deposition and brain atrophy, and more rapid disease progression (17). APOE not only involve in the aggregation and clearance of Aβ but also participate in the regulation of microglial activation, immune regulation and cytokine release (46). However, the role of APOE in synaptic clearance and neural pathway regulation needs to be further explored.

Furthermore, the complement system has recently been shown to plays both neuroprotective and neuroinflammatory roles in AD pathophysiology (47). During the early stages of AD, the complement system can succeed in clearing Aβ in conjunction with glial cells (48). However, when Aβ starts to accumulate and Aβ plaques develop, the complement system can further increase the phagocytic capability of microglia (49). Here, we will discuss how the complement system is involved in the effective functioning of microglia-mediated synaptic clearance in Alzheimer’s disease.

As the most important immune cells in the brain, microglia play significant roles in almost all central nervous system disease processes. The studies of microglia function have been a hot topic in the field of AD research. Microglia can refine synaptic connections through phagocytosis to ensure accurate transmission of information. TREM2, a microglia surface receptor, is essential for synaptic clearance by microglia, but the exact mechanism needs to be further explored. TREM2 binds with high affinity to APOE and promotes the clearance of apoptotic neurons and cellular debris by microglia. Previous studies have identified the complement signaling pathway is also involved in synaptic clearance. APOE may affect the classic complement cascade through the C1q-APOE complex, which affects microglia and influences synaptic pruning. In recent years, significantly increased levels of both TREM2 and the complement protein C1q have been found around Aβ, suggesting an association between TREM2 and C1q. Therefore, we propose that TREM2, APOE and C1q interact with each other and promote microglia mediated synaptic clearance in AD Figure 1.

In this review, we systematically summarized the potential mechanisms of microglia involved in synaptic clearance, comprehensively reviewed the role of TREM2 in microglia regulating synaptic clearance and proposed our hypothesis that TREM2 interacts with APOE and C1q to promote synaptic clearance in AD. This review provides new insights into the role of TREM2 regulation in microglia synaptic clearance and provides new clues to elucidate the role of TREM2 in the pathogenesis of AD.

QQ: Conceptualization, Writing - review and editing, Supervision. MW: Conceptualization, Writing - original draft, Writing - review and editing. YY: Writing - original draft. YT: Conceptualization, Writing - review and editing, Supervision, Project administration. All authors read and approved the final manuscript.

This work was supported by Capital’s Funds for HealthImprovement and Research [grant number CFH 2020-4-1033]; Beijing NOVA Program [grant number Z211100002121051];Beijing Hospitals Authority Innovation Studio of Young Staff Funding Support [grant number 202118] and Young Elite Scientists Sponsorship Program by CAST [grant number 2021QNRC001].

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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