The Specific Mechanism of TREM2 Regulation of Synaptic Clearance in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease. Synaptic dysfunction is an integral feature of AD pathophysiology and a significant factor in early cognitive impairment in AD. Microglia, which are intrinsic immune cells in the central nervous system, play important regulatory roles in the process of synapse formation. Microglia can refine synaptic connections through synaptic clearance to ensure accurate synaptic transmission. Synaptic clearance is not only existed during central nervous system development but also aberrantly activated during AD pathology. However, the mechanisms of synaptic clearance in AD remain to be investigated. TREM2 is involved in the synaptic clearance of microglia, acting alone or with other molecules, such as apolipoprotein E (APOE). In addition, C1q is essential for microglia-mediated synaptic clearance. 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. This review provides new insights into the role of TREM2 regulation in microglia synaptic clearance and provides potential prospects for the treatment of AD.

Microglia as a cellular target of diclofenac therapy in Alzheimer’s disease

“… 37 , 40 Emerging data identified TREM2 as a potential ligand for neuronal ApoE, linking neuroinflammation and microglia activity directly to the ApoE ε4 allele, the strongest known genetic risk factor of late-onset AD. 40 …”

C1q and central nervous system disorders

“…Alzheimer’s disease (AD) is a common neurodegenerative disorder that affects the elderly, but its underlying mechanisms are still not fully understood. The cognitive impairment observed in AD is associated with synaptic loss and morphological changes in the brain ( 93 ). A study of cerebrospinal fluid from patients with AD pathology (beta-amyloid (Ab) and tau subtypes) but not yet symptomatic or in pre-dementia found elevated YKL-40, sTREM2, sAXL, sTyro3, MIF, complement factors C1q, C4 and H, ferritin, and ApoE inflammatory markers ( 61 ).…”

“…A study of cerebrospinal fluid from patients with AD pathology (beta-amyloid (Ab) and tau subtypes) but not yet symptomatic or in pre-dementia found elevated YKL-40, sTREM2, sAXL, sTyro3, MIF, complement factors C1q, C4 and H, ferritin, and ApoE inflammatory markers ( 61 ). C1q has been found to induce excessive phagocytosis and synapse clearance by microglia, leading to synapse loss in AD patients ( 93 , 94 ). Carpanini et al.…”

Recent advances in the use of CRISPR/Cas for understanding the early development of molecular gaps in glial cells

“…It has been reported that microglial complement receptor CR3/ Mac1 and triggering receptor expressed on myeloid cells 2 (TREM2) contribute to synaptic pruning (Qin et al, 2022). Scott-Hewitt et al (2020) proposed that the recognition of exposed phosphatidylserine in neurons is crucial for microglial-mediated pruning, and some possible candidates as synapse pruning mediators are the isoform of adhesion G protein-coupled receptor (ADGRG1/GPR56) and TREM2; however, the molecular mechanisms involved in microglia target neuron selection are unknown (Li et al, 2020;Scott-Hewitt et al, 2020;Qin et al, 2022).…”

“…It has been reported that microglial complement receptor CR3/ Mac1 and triggering receptor expressed on myeloid cells 2 (TREM2) contribute to synaptic pruning (Qin et al, 2022). Scott-Hewitt et al (2020) proposed that the recognition of exposed phosphatidylserine in neurons is crucial for microglial-mediated pruning, and some possible candidates as synapse pruning mediators are the isoform of adhesion G protein-coupled receptor (ADGRG1/GPR56) and TREM2; however, the molecular mechanisms involved in microglia target neuron selection are unknown (Li et al, 2020;Scott-Hewitt et al, 2020;Qin et al, 2022). On the other hand, it should be noted that TREM2 and the complement cascade have been associated with the progression of Alzheimer's disease (AD), as mouse models have shown the importance of TREM2 for the microglial phagocytosis response in amyloid seeds (Smidt et al, 2007;Flores-Fernández et al, 2018;Parhizkar et al, 2019;Ewers et al, 2020;Meilandt et al, 2020;Scott-Hewitt et al, 2020;Yang et al, 2020).…”