阿尔茨海默病中小胶质细胞相关易感基因及其作用机制的研究进展

doi:10.13481/j.1671-587X.20250131

Abstract

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-related susceptibility genes related to AD and their regulatory mechanisms.

Key words: Alzheimer’s disease, Microglia, Susceptibility genes, Phagocytosis, Lipid metabolism, Immune response

CLC Number:

R749.16

Kuai WANG,Yu YANG. Research progress in microglia-related susceptibility genes in Alzheimer’s disease and their mechanisms[J].Journal of Jilin University(Medicine Edition), 2025, 51(1): 255-265.

Figures/Tables 1

Tab.1

Microglia-related AD susceptibility genes and their functional regulation"

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 endocy tosis

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]

Tab.1

References 52

1	KNOPMAN D S， AMIEVA H， PETERSEN R C，et al. Alzheimer disease［J］.Nat Rev Dis Primers，2021，7（1）： 33.
2	LI M L， WU S H， SONG B， et al. Single-cell analysis reveals transcriptomic reprogramming in aging primate entorhinal cortex and the relevance with Alzheimer’s disease［J］. Aging Cell， 2022， 21（11）： e13723.
3	GAO C， JIANG J W， TAN Y Y， et al. Microglia in neurodegenerative diseases： mechanism and potential therapeutic targets［J］. Signal Transduct Target Ther， 2023， 8（1）： 359.
4	BELLENGUEZ C， KÜÇÜKALI F， JANSEN I E，et al. New insights into the genetic etiology of Alzheimer’s disease and related dementias［J］. Nat Genet， 2022， 54（4）： 412-436.
5	ANDREWS S J， RENTON A E， FULTON-HOWARD B， et al. The complex genetic architecture of Alzheimer’s disease： novel insights and future directions［J］.EBioMedicine， 2023， 90： 104511.
6	NOVIKOVA G， KAPOOR M， TCW J， et al. Integration of Alzheimer’s disease genetics and myeloid genomics identifies disease risk regulatory elements and genes［J］. Nat Commun， 2021， 12（1）： 1610.
7	SCHWARTZENTRUBER J， COOPER S， LIU J Z， et al. Genome-wide meta-analysis， fine-mapping， and integrative prioritization implicate new Alzheimer’s disease risk genes［J］. Nat Genet， 2021，53（3）： 392-402.
8	DECZKOWSKA A， WEINER A， AMIT I. The physiology， pathology， and potential therapeutic applications of the TREM2 signaling pathway［J］. Cell， 2020， 181（6）： 1207-1217.
9	YEH F L， WANG Y Y， TOM I， et al. TREM2 binds to apolipoproteins， including APOE and CLU/APOJ， and thereby facilitates uptake of amyloid-Beta by microglia［J］. Neuron， 2016， 91（2）： 328-340.
10	FRANK S， BURBACH G J， BONIN M， et al. TREM2 is upregulated in amyloid plaque-associated microglia in aged APP23 transgenic mice［J］. Glia， 2008， 56（13）： 1438-1447.
11	KEREN-SHAUL H， SPINRAD A， WEINER A，et al. A unique microglia type associated with restricting development of Alzheimer’s disease［J］. Cell， 2017， 169（7）： 1276-1290.e17.
12	ULLAND T K， SONG W M， HUANG S C C， et al. TREM2 maintains microglial metabolic fitness in Alzheimer’s disease［J］. Cell， 2017， 170（4）： 649-663.e13.
13	RIVEST S. TREM2 enables amyloid β clearance by microglia［J］. Cell Res， 2015， 25（5）： 535-536.
14	WANG Y M， ULLAND T K， ULRICH J D， et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques［J］. J Exp Med， 2016， 213（5）： 667-675.
15	YUAN P， CONDELLO C， KEENE C D， et al. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy［J］. Neuron， 2016， 90（4）： 724-739.
16	Daniel LEE C Y， DAGGETT A， GU X， et al. Elevated TREM2 gene dosage reprograms microglia responsivity and ameliorates pathological phenotypes in Alzheimer’s disease models［J］. Neuron， 2018， 97（5）： 1032-1048.e5.
17	JAIN N， LEWIS C A， ULRICH J D， et al. Chronic TREM2 activation exacerbates Aβ-associated tau seeding and spreading［J］. J Exp Med， 2023， 220（1）： e20220654.
18	HOU J， CHEN Y， GRAJALES-REYES G， et al. TREM2 dependent and independent functions of microglia in Alzheimer’s disease ［J］. Mol Neurodegener， 2022， 17（1）： 84.
19	KORVATSKA O， KIIANITSA K， RATUSHNY A， et al. Triggering receptor expressed on myeloid cell 2 R47H exacerbates immune response in Alzheimer’s disease brain［J］. Front Immunol， 2020， 11： 559342.
20	SAYED F A， KODAMA L， FAN L， et al. AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation［J］. Sci Transl Med， 2021， 13（622）： eabe3947.
21	SERRANO-POZO A， DAS S， HYMAN B T. APOE and Alzheimer’s disease： advances in genetics， pathophysiology， and therapeutic approaches［J］. The Lancet， Neurol， 2021， 20（1）： 68-80.
22	LIU C C， LIU C C， KANEKIYO T， et al. Apolipoprotein E and Alzheimer disease： risk， mechanisms and therapy［J］. Nat Rev， Neurol， 2013，9（2）： 106-118.
23	TCW J， QIAN L， PIPALIA N H， et al. Cholesterol and matrisome pathways dysregulated in astrocytes and microglia［J］. Cell， 2022， 185（13）： 2213-2233.e25.
24	LIN Y T， SEO J， GAO F， et al. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types［J］. Neuron， 2018， 98：1141-1154.e7.
25	QIAN X H， CHEN S Y， LIU X L， et al. ABCA7-associated clinical features and molecular mechanisms in Alzheimer’s disease［J］. Mol Neurobiol， 2023， 60（10）：5548-5556.
26	ROECK A D， VAN BROECKHOVEN C， SLEEGERS K. The role of ABCA7 in Alzheimer’s disease： evidence from genomics， transcriptomics and methylomics［J］. Acta Neuropathol， 2019， 138（2）： 201-220.
27	JIAO B， XIAO X W， YUAN Z H， et al. Associations of risk genes with onset age and plasma biomarkers of Alzheimer’s disease： a large case-control study in mainland China［J］. Neuropsychopharmacology， 2022， 47（5）： 1121-1127.
28	SAKAE N， LIU C C， SHINOHARA M， et al. ABCA7 deficiency accelerates amyloid-β generation and Alzheimer’s neuronal pathology［J］. J Neurosci， 2016， 36（13）： 3848-3859.
29	AIKAWA T， REN Y X， YAMAZAKI Y， et al. ABCA7 haplodeficiency disturbs microglial immune responses in the mouse brain［J］. Proc Nat Acad Sci U S A， 2019， 116（47）： 23790-23796.
30	FU Y， HSIAO J H T， PAXINOS G， et al. ABCA7 mediates phagocytic clearance of amyloid-β in the brain［J］. J Alzheimers Dis： JAD，2016，54（2）： 569-584.
31	ESKANDARI-SEDIGHI G， JUNG J， MACAULEY M S. CD33 isoforms in microglia and Alzheimer’s disease： friend and foe［J］. Mol Aspect Med， 2023， 90： 101111.
32	GRICIUC A， SERRANO-POZO A， PARRADO A R， et al. Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta［J］. Neuron， 2013， 78（4）： 631-643.
33	BHATTACHERJEE A， JUNG J， ZIA S， et al. The CD33 short isoform is a gain-of-function variant that enhances Aβ1-42 phagocytosis in microglia［J］. Mol Neurodegener， 2021， 16（1）： 19.
34	TORTORA F， RENDINA A， ANGIOLILLO A，et al. CD33 rs2455069 SNP： correlation with Alzheimer’s disease and hypothesis of functional role［J］. Int J Mol Sci， 2022， 23（7）： 3629.
35	MATTIOLA I， MANTOVANI A， LOCATI M. The tetraspan MS4A family in homeostasis， immunity， and disease［J］. Trends Immunol， 2021， 42（9）： 764-781.
36	DEMING Y， FILIPELLO F， CIGNARELLA F，et al. The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk［J］. Sci Transl Med， 2019， 11（505）： eaau2291.
37	BRASE L， YOU S F， D’OLIVEIRA ALBANUS R D， et al. Single-nucleus RNA-sequencing of autosomal dominant Alzheimer disease and risk variant carriers［J］. Nat Commun， 2023， 14（1）： 2314.
38	PIMENOVA A A， HERBINET M， GUPTA I， et al. Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response［J］. Neurobiol Dis， 2021， 148： 105217.
39	VAN ACKER Z P， BRETOU M， ANNAERT W. Endo-lysosomal dysregulations and late-onset Alzheimer’s disease： impact of genetic risk factors［J］. Mol Neurodegener， 2019， 14（1）： 20.
40	SUDWARTS A， RAMESHA S， GAO T W， et al. BIN1 is a key regulator of proinflammatory and neurodegeneration-related activation in microglia［J］. Mol Neurodegener， 2022， 17（1）： 33.
41	MENDSAIKHAN A， TOOYAMA I， WALKER D G. Microglial progranulin： involvement in Alzheimer’s disease and neurodegenerative diseases［J］. Cells， 2019， 8（3）： 230.
42	ROMERO-MOLINA C， GARRETTI F， ANDREWS S J， et al. Microglial efferocytosis： Diving into the Alzheimer’s disease gene pool［J］.Neuron，2022，110（21）：3513-3533.
43	ULRICH J D， ULLAND T K， COLONNA M， et al. Elucidating the role of TREM2 in Alzheimer’s disease［J］. Neuron， 2017， 94（2）： 237-248.
44	CAMPION D， CHARBONNIER C， NICOLAS G. SORL1 genetic variants and Alzheimer disease risk： a literature review and meta-analysis of sequencing data［J］. Acta Neuropathol， 2019， 138（2）： 173-186.
45	ZHU X C， YU J T， JIANG T， et al. CR1 in Alzheimer’s disease［J］. Mol Neurobio， 2015， 51（2）： 753-765.
46	LI K， RAN B， WANG Y， et al. PLCγ2 impacts microglia-related effectors revealing variants and pathways important in Alzheimer’s disease［J］. Front Cell Dev Biol， 2022，10：999061.
47	RATHORE N， RAMANI S R， PANTUA H， et al. Paired immunoglobulin-like Type 2 Receptor Alpha G78R variant alters ligand binding and confers protection to Alzheimer’s disease［J］. PLoS Genet， 2018，14（11）： e1007427.
48	HAROLD D， ABRAHAM R， HOLLINGWORTH P， et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease， and shows evidence for additional susceptibility genes［J］. Nat Genet， 2009， 41（10）： 1088-1093.
49	PADHY B， KAPUGANTI R S， HAYAT B， et al. Wide-spread enhancer effect of SNP rs2279590 on regulating epoxide hydrolase-2 and protein tyrosine kinase 2-beta gene expression［J］. Gene， 2023， 854： 147096.
50	KARAHAN H， SMITH D C， KIM B， et al. Deletion of Abi3 gene locus exacerbates neuropathological features of Alzheimer’s disease in a mouse model of Aβ amyloidosis［J］. Sci Adv， 2021， 7（45）： eabe3954.
51	LI Y H， LAWS S M， MILES L A， et al. Genomics of Alzheimer’s disease implicates the innate and adaptive immune systems［J］. Cell Mol Life Sci， 2021， 78（23）： 7397-7426.
52	SMITH A M， DAVEY K， TSARTSALIS S， et al. Diverse human astrocyte and microglial transcriptional responses to Alzheimer’s pathology［J］. Acta Neuropathol， 2022， 143（1）： 75-91.

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