阿尔茨海默症中小胶质细胞相关易感基因及其作用机制的研究进展

摘要/Abstract

摘要：

小胶质细胞作为中枢神经系统固有的免疫细胞，在阿尔茨海默症（AD）中发挥免疫应答功能，一方面吞噬清除异常蛋白及凋亡神经元，避免损伤进一步扩大，另一方面诱导慢性神经炎症，进一步加剧病理损伤。以往的研究认为小胶质细胞激活后的功能变化是AD病理所引起的，然而近年来基因组学的发现打破这一认知。大规模全基因组关联分析（GWAS）和全基因组/外显子测序研究已经明确了70余个AD风险位点。在这些风险基因座中，大部分基因变体参与编码小胶质细胞功能相关分子或影响小胶质细胞功能基因的转录活性。功能及通路分析发现上述风险位点主要富集在调控小胶质细胞吞噬功能、脂质代谢和免疫应答等功能的信号通路上，提示小胶质细胞不仅作为对AD病理的“应答者”，同时也是AD病理发生的“参与者”。对上述易感基因的深入研究有助于进一步拓展小胶质细胞在AD的调控机制与功能谱。现基于遗传学研究对目前发现的小胶质细胞相关AD易感基因及其调节机制进行综述。

关键词: 阿尔茨海默症, 小胶质细胞, 易感基因, 吞噬作用, 脂质代谢, 免疫应答

Abstract:

Microglia， as intrinsic immune cells of the central nervous system， play an immune response function in Alzheimer’s disease （AD），which prevents further damages by eliminating abnormal proteins and apoptotic neurons while also leads pathological progression via inducing chronic neuroinflammation.The previous studies have suggested that the functional changes of microglia activation are initiated by AD pathologies. However，the recent genomic studies have challenged this understanding. Large-scale genome-wide association analysis （GWAS） and whole genome/exome sequencing studies have identified more than 70 risk loci of AD. Among these risk loci， most gene variants are involved in encoding microglia function-related molecules or affecting the transcriptional activity of genes associated with the microglial biofunctions.The functional and pathway analysis results have revealed that these risk loci are mainly enriched in signaling pathways regulating microglia phagocytosis， lipid metabolism， and immune response， suggesting that microglia not only act as a “responder” to AD pathologies， but also a “participant” in the development of AD pathogenesis.In-depth studies of these susceptibility genes may further expand our understanding of the regulatory mechanisms and functional spectrum of microglia in AD. This review is based on genetic studies and summarizes the current knowledge of microglial risk genes related to AD and their regulatory mechanisms.

Key words: Alzheimer’s disease, microglia, risk genes, phagocytosis, lipid metabolism, immune response

中图分类号:

R749.16

王快, 杨宇. 阿尔茨海默症中小胶质细胞相关易感基因及其作用机制的研究进展[J]. 吉林大学学报(医学版), 2024, (): 1-11.

Kuai WANG, Yu YANG. Research progress in microglia-related risk genes in Alzheimer’s disease and their mechanisms[J]. Journal of Jilin University(Medicine Edition), 2024, (): 1-11.

图/表 1

表1

小胶质细胞相关的AD易感基因及其功能调节"

Gene	Protein function in AD	Risk variant	Variants effect on microglial function	AD risk	Reference
TREM2（6p21.1）	Phagocytosis Immune response Metabolic fitness	rs75932628 rs143332484 rs10947943	Impaired phagocytosis Neuroinflammation Reduces mitochondrial respiratory capacity and glycolytic metabolic	Increase	^[4,44]
SORL1（11q24.1）	Functions as endosomal trafficking receptor and mediates endocytosis Intracellular APP transportation and proteolysis	rs11218343 rs74685827	Impaired endocytosis Affects DAM transition	Increase	^[4,45]
CD33（19q13.41）	Binds sialic acids and inhibits phagocytosis mediated by TREM2 Immune response	rs3865444 rs12459419	Alteration in alternative splicing of CD33 Affects activation of TREM2/DAP12 signaling pathway	Increase/Decrease	^[31]
CR1（1q32.2）	Complement receptor for C3b/C4b and C1q Promotes phagocytosis as an opsonin	rs679515 rs3818361 rs6656401	Reduces induced Aβ clearance by complement Affects complement system cascade	Increase	^[4,46]
PLCG2（16q24.1）	Acts downstream of TREM2 signaling pathway Intracellular calcium release	rs72824905 rs12446759	Regulates phagocytosis Regulates DAM related genes expression	Increase/Decrease	^[47]
MS4A（11q12.2）	Intracellular protein trafficking Lipid sensing Phagocytosis	rs6591561 rs1582763	Related to TREM2 processing Associated with the level of sTREM2 Immune response /complement system	Increase/Decrease	^[36]
PILRA（7q22.1）	Binds sialic acids and inhibits phagocytosis mediated by TREM2 Mediates invasion of HSV-1 into cells	rs1859788	Reduces inhibitory signaling in microglia Reduces microglial infection during HSV-1 recurrence	Decrease	^[48]
CLU/APOJ（8p21.1）	Bind Aβ and lipids Phagocytosis Lipids metabolism Immune response	rs11787077 rs11136000 rs2279590	Reduces Aβ phagocytic clearance	Increase	^[4,49-50]
PICALM（11q14.2）	Endo-lysosomal trafficking Lipids metabolism	rs3851179	Rescues endocytic defects caused by APOE4 Regulates microglial lipid droplet formation	Decrease	^[49]
ABI3 （17q21.32）	Cytoskeleton rearrangement Focal adhesion Cell migration Phagocytosis	rs616338	Impairs microglial migration and phagocytosis Increases Aβ deposition	Increase	^[51]
B1N1（2q14.3）	Endo-lysosomal trafficking Cytoskeleton	rs6733839	Impaired phagocytosis Promotes inflammation	Increase	^[40]
ZYX（7q34-q35）	Actin cytoskeletal rearrangement Cell migration Synaptic development and plasticity	rs11771145	Affects immune response and endocytosis Disruption of the blood-brain barrier integrity	Increase	^[52]
GRN（17q21）	Lysosomal degradation	rs5848	Lysosomal dysfunction Lipid dysregulation Microglial hyperactivation	Increase	^[41]
APOE（19q13.2）	Acts as an opsonin and facilitates Phagocytosis Mediates cholesterol efflux	rs429358 rs7412	Affects lipid transportation and cholesterol efflux Affects immune response Enhances or reduces Aβ phagocytosis	Increase/Decrease	^[21]
ABCA7（19p13.3）	Lipids metabolism/Lipids homeostasis Immune response Aβ phagocytosis and clearance	rs12151021 rs3752246 rs115550680	Abnormal lipid metabolism Promotes APP processing into Aβ Reduced microglial clearance of Aβ	Increase	^[4,25]
INPP5D\|（2q.37.1）	Interacts with DAP12 and inhibits downstream of TREM2 signaling pathway	rs10933431	Reduces inhibitory signaling of TREM2	Decrease	^[52]
SPI1/PU.1 （11p11.2）	Regulates microglial transcriptome	rs10437655 rs3740688	Decreases PU.1 expression and regulates microglial inflammatory response	Decrease	^[52]
HLA-DRB1（6p21.32）	Involves in immune responses including antigen processing and presentation, as well as immune cell self-recognition	rs9271058	Induces microglial activation	Increase	^[52]

表1

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