Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disease, accounting for 60–70% of dementia cases globally. Inflammation of the central nervous system (CNS) caused by microglia is a common characteristic of neurodegenerative illnesses such as Parkinson's disease and AD. Research has recently examined the relationship between neurodegenerative diseases and CNS microglia. Microglial cells comprise 10–15% of all CNS cells and are brain-resident myeloid cells mediating critical processes to support the CNS. Microglia have a variety of receptors that operate as molecular sensors, detecting exogenous and endogenous CNS injuries and triggering an immune response. Microglia serve as brain guardians by boosting phagocytic clearance and providing trophic support to enable tissue repair and maintain cerebral homeostasis, in addition to their traditional immune cell activity. At rest, microglia manage CNS homeostasis by phagocytic action, which removes pathogens and cell debris. Microglia cells that have been "resting" convert into active cells that create inflammatory mediators, protecting neurons and protecting against invading pathogens. Neuronal damage and neurodegenerative disorders are caused by excessive inflammation. Different microglial cells reply at different phases of the disease can lead to new therapy options and reduced inflammatory activity. This review focuses on the potential function of microglia, microglia subtypes, and M1/M2 phenotypic changes associated with neurodegenerative disorders. Microglial membrane receptors, the involvement of microglia in neuroinflammation, microglial targets in AD and the double role of microglia in AD pathogenesis are also discussed in this review.
Graphical Abstract
[http://dx.doi.org/10.1017/S135561771700100X] [PMID: 29198280]
[http://dx.doi.org/10.1016/j.jalz.2018.02.001]
[http://dx.doi.org/10.1016/j.jalz.2017.12.006] [PMID: 29433981]
[http://dx.doi.org/10.1136/bmjopen-2016-012759]
[http://dx.doi.org/10.1080/14737175.2018.1476140] [PMID: 29764230]
[http://dx.doi.org/10.1080/01616412.2016.1209337] [PMID: 27431920]
[http://dx.doi.org/10.1080/14740338.2020.1721456] [PMID: 31976781]
[http://dx.doi.org/10.2174/1381612825666191011102444] [PMID: 31604413]
[http://dx.doi.org/10.1016/0923-2494(92)80050-U] [PMID: 1455057]
[http://dx.doi.org/10.1091/mbc.e10-09-0745] [PMID: 21441306]
[http://dx.doi.org/10.2353/ajpath.2009.090418] [PMID: 19834064]
[http://dx.doi.org/10.1111/bpa.12456] [PMID: 27862631]
[http://dx.doi.org/10.1016/j.neuron.2018.05.014] [PMID: 29861285]
[http://dx.doi.org/10.1038/nn.3599] [PMID: 24316888]
[http://dx.doi.org/10.1073/pnas.1525528113] [PMID: 26884166]
[http://dx.doi.org/10.1126/science.aal3222]
[http://dx.doi.org/10.1016/j.cell.2018.04.018] [PMID: 29779944]
[http://dx.doi.org/10.1002/glia.23575] [PMID: 30588668]
[http://dx.doi.org/10.1038/nri3705] [PMID: 24962261]
[http://dx.doi.org/10.1016/j.neurobiolaging.2017.03.021] [PMID: 28434692]
[http://dx.doi.org/10.1186/s40478-014-0142-6] [PMID: 25257319]
[http://dx.doi.org/10.1002/glia.23318] [PMID: 29493017]
[http://dx.doi.org/10.1093/brain/awp177] [PMID: 19567702]
[http://dx.doi.org/10.1007/s00401-013-1242-2] [PMID: 24407428]
[http://dx.doi.org/10.1016/j.cell.2017.05.018] [PMID: 28602351]
[http://dx.doi.org/10.1016/j.neurobiolaging.2016.07.028] [PMID: 27658901]
[http://dx.doi.org/10.1038/s41586-019-1195-2] [PMID: 31042697]
[http://dx.doi.org/10.1111/bpa.12717] [PMID: 30803086]
[http://dx.doi.org/10.1038/ncomms11295] [PMID: 27097852]
[http://dx.doi.org/10.1101/610345]
[http://dx.doi.org/10.1016/j.celrep.2017.12.066] [PMID: 29346778]
[http://dx.doi.org/10.1080/19420889.2016.1230575] [PMID: 28042375]
[http://dx.doi.org/10.1002/glia.22966] [PMID: 26847266]
[http://dx.doi.org/10.3389/fimmu.2018.00803] [PMID: 29922276]
[http://dx.doi.org/10.1007/s00401-016-1630-5] [PMID: 27743026]
[http://dx.doi.org/10.3389/fnagi.2018.00140] [PMID: 29867449]
[http://dx.doi.org/10.1002/glia.23024] [PMID: 27404378]
[http://dx.doi.org/10.1038/mp.2017.246] [PMID: 29230021]
[http://dx.doi.org/10.1038/nn.4338] [PMID: 27459405]
[http://dx.doi.org/10.1186/s12974-016-0581-z] [PMID: 27220367]
[http://dx.doi.org/10.1186/s13024-017-0197-5] [PMID: 28768545]
[http://dx.doi.org/10.1038/nn.4597] [PMID: 28671693]
[http://dx.doi.org/10.1016/j.celrep.2017.09.039] [PMID: 29020624]
[http://dx.doi.org/10.1038/s41467-018-02926-5] [PMID: 29416036]
[http://dx.doi.org/10.1038/s41380-019-0609-8] [PMID: 31772305]
[http://dx.doi.org/10.1007/s00401-019-02048-2] [PMID: 31350575]
[http://dx.doi.org/10.1016/j.neuron.2018.02.002] [PMID: 29518357]
[http://dx.doi.org/10.1016/j.immuni.2017.08.008] [PMID: 28930663]
[http://dx.doi.org/10.1523/JNEUROSCI.0616-08.2008] [PMID: 18701698]
[http://dx.doi.org/10.1186/s13024-016-0137-9] [PMID: 27887626]
[http://dx.doi.org/10.1056/NEJMoa1211851] [PMID: 23150934]
[http://dx.doi.org/10.1038/nn.4142] [PMID: 26505565]
[http://dx.doi.org/10.3390/ijms19010318] [PMID: 29361745]
[http://dx.doi.org/10.1084/jem.20160844] [PMID: 28209725]
[http://dx.doi.org/10.1038/ni1411] [PMID: 17110943]
[http://dx.doi.org/10.1016/j.neuron.2018.01.031] [PMID: 29518356]
[http://dx.doi.org/10.1038/npp.2014.164] [PMID: 25047746]
[http://dx.doi.org/10.1523/JNEUROSCI.2459-16.2017] [PMID: 28077724]
[http://dx.doi.org/10.1186/s12974-017-0835-4] [PMID: 28320424]
[http://dx.doi.org/10.1038/nn.4126] [PMID: 26414614]
[http://dx.doi.org/10.1159/000492596] [PMID: 30541012]
[http://dx.doi.org/10.1111/j.1749-6632.2011.06449.x] [PMID: 22352893]
[http://dx.doi.org/10.1007/s12035-013-8536-1] [PMID: 23982747]
[http://dx.doi.org/10.1016/j.neuron.2019.06.010] [PMID: 31301936]
[http://dx.doi.org/10.1007/s12035-014-8880-9] [PMID: 25186233]
[http://dx.doi.org/10.1038/nn.3435] [PMID: 23708142]
[http://dx.doi.org/10.1016/j.neuron.2013.04.014] [PMID: 23623698]
[http://dx.doi.org/10.1007/s10571-014-0101-6] [PMID: 25149075]
[http://dx.doi.org/10.1074/jbc.M109.007849] [PMID: 19369259]
[http://dx.doi.org/10.1523/JNEUROSCI.1569-12.2012] [PMID: 23197723]
[http://dx.doi.org/10.1074/jbc.M702887200] [PMID: 17623670]
[http://dx.doi.org/10.1038/nm.3159] [PMID: 23652116]
[http://dx.doi.org/10.1186/s12974-018-1250-1] [PMID: 30029608]
[http://dx.doi.org/10.1074/jbc.R300028200] [PMID: 12893815]
[http://dx.doi.org/10.1523/JNEUROSCI.23-07-02665.2003] [PMID: 12684452]
[http://dx.doi.org/10.1038/ncomms3030] [PMID: 23799536]
[http://dx.doi.org/10.1111/j.1462-5822.2009.01326.x] [PMID: 19388903]
[http://dx.doi.org/10.1038/nri3515] [PMID: 23928573]
[http://dx.doi.org/10.1016/j.bbi.2017.12.007] [PMID: 29246456]
[http://dx.doi.org/10.1084/jem.20162011] [PMID: 28298456]
[http://dx.doi.org/10.1016/j.neuron.2012.03.026] [PMID: 22632727]
[http://dx.doi.org/10.1084/jem.20190009] [PMID: 31209071]
[http://dx.doi.org/10.1016/j.neuron.2019.01.014] [PMID: 30737131]
[http://dx.doi.org/10.1126/science.aad8373] [PMID: 27033548]
[http://dx.doi.org/10.1002/glia.22331] [PMID: 22438044]
[http://dx.doi.org/10.1111/j.1749-6632.1999.tb07696.x] [PMID: 10415742]
[http://dx.doi.org/10.1002/ca.980080612] [PMID: 8713166]
[http://dx.doi.org/10.1038/srep14624] [PMID: 26416689]
[http://dx.doi.org/10.1186/1750-1326-6-45] [PMID: 21718498]
[http://dx.doi.org/10.1038/s41586-019-1088-4] [PMID: 30944478]
[PMID: 19838177]
[http://dx.doi.org/10.4049/jimmunol.1700373] [PMID: 28483986]
[http://dx.doi.org/10.1073/pnas.76.1.333] [PMID: 218198]
[http://dx.doi.org/10.1161/01.CIR.101.20.2411] [PMID: 10821819]
[http://dx.doi.org/10.1007/s00011-011-0433-3] [PMID: 22240665]
[http://dx.doi.org/10.1016/S0896-6273(00)80187-7] [PMID: 8816718]
[http://dx.doi.org/10.1016/S0197-4580(98)00036-0] [PMID: 9562474]
[http://dx.doi.org/10.1038/s41598-017-11634-x] [PMID: 28127051]
[http://dx.doi.org/10.1021/acschemneuro.6b00386] [PMID: 28150942]
[http://dx.doi.org/10.1073/pnas.1015413108] [PMID: 21383152]
[http://dx.doi.org/10.1006/exnr.2001.7732] [PMID: 11520119]
[http://dx.doi.org/10.1371/journal.pone.0225487] [PMID: 33119615]
[http://dx.doi.org/10.1172/JCI58642] [PMID: 22406537]
[http://dx.doi.org/10.1155/2013/895651] [PMID: 23737655]
[http://dx.doi.org/10.1523/JNEUROSCI.1860-14.2014] [PMID: 25186741]
[http://dx.doi.org/10.3233/JAD-160083] [PMID: 27258416]
[http://dx.doi.org/10.1007/s00401-020-02200-3] [PMID: 32840654]
[http://dx.doi.org/10.1002/glia.20772] [PMID: 18803301]
[http://dx.doi.org/10.1084/jem.20171265] [PMID: 29483128]
[http://dx.doi.org/10.1186/s13024-015-0048-1] [PMID: 26438529]
[http://dx.doi.org/10.1007/s12035-014-8723-8] [PMID: 24794147]
[http://dx.doi.org/10.1016/j.nbd.2013.02.003] [PMID: 23454195]
[http://dx.doi.org/10.1016/j.annonc.2020.04.200]
[http://dx.doi.org/10.1016/j.cell.2017.07.023] [PMID: 28802038]
[http://dx.doi.org/10.1016/j.nicl.2018.101621] [PMID: 30528368]
[http://dx.doi.org/10.1073/pnas.1908529116] [PMID: 31690660]
[http://dx.doi.org/10.1016/j.nbd.2021.105303] [PMID: 33631273]
[http://dx.doi.org/10.3233/JAD-150704] [PMID: 26638867]
[http://dx.doi.org/10.1038/srep11161] [PMID: 26057852]
[http://dx.doi.org/10.3390/biom10101439] [PMID: 33066368]
[PMID: 33413517]
[http://dx.doi.org/10.3389/fncel.2018.00172] [PMID: 30042659]
[http://dx.doi.org/10.1002/glia.21091] [PMID: 21125642]
[http://dx.doi.org/10.1016/j.neuron.2010.08.023] [PMID: 20920788]
[http://dx.doi.org/10.1038/s41593-019-0433-0] [PMID: 31235932]
[http://dx.doi.org/10.1007/s00401-009-0556-6] [PMID: 19513731]
[http://dx.doi.org/10.1038/s41586-018-0543-y] [PMID: 30232451]
[http://dx.doi.org/10.1007/978-981-32-9358-8_17] [PMID: 32096040]
[http://dx.doi.org/10.1093/brain/awv081] [PMID: 25833819]
[http://dx.doi.org/10.1038/nn.4132] [PMID: 26436904]
[http://dx.doi.org/10.1038/s41593-018-0332-9] [PMID: 30742114]
[http://dx.doi.org/10.1016/j.bbi.2020.09.017] [PMID: 32971182]
[http://dx.doi.org/10.1002/glia.23568] [PMID: 30582668]
[http://dx.doi.org/10.1007/s004290050280] [PMID: 10463344]
[PMID: 12572918]
[http://dx.doi.org/10.3390/ijerph8072980] [PMID: 21845170]
[http://dx.doi.org/10.4061/2010/732806]
[http://dx.doi.org/10.1186/1750-1326-4-47] [PMID: 19917131]
[http://dx.doi.org/10.1016/j.cell.2010.02.016] [PMID: 20303880]
[http://dx.doi.org/10.1007/s12035-015-9593-4] [PMID: 26659872]
[PMID: 30444278]
[http://dx.doi.org/10.1038/nn.4547] [PMID: 28414331]
[http://dx.doi.org/10.1186/s40478-018-0584-3] [PMID: 30185219]
[http://dx.doi.org/10.1016/j.cell.2018.05.003] [PMID: 29775591]
[http://dx.doi.org/10.1038/s41586-019-0924-x] [PMID: 30760929]
[http://dx.doi.org/10.1083/jcb.201709069] [PMID: 29196460]
[http://dx.doi.org/10.1038/nn.3318] [PMID: 23334579]
[http://dx.doi.org/10.1016/j.ejcb.2017.03.004] [PMID: 28336086]
[http://dx.doi.org/10.1016/j.nlm.2013.07.002] [PMID: 23850597]
[http://dx.doi.org/10.1016/j.bbi.2009.10.018] [PMID: 19903519]
[http://dx.doi.org/10.1097/WNR.0000000000001032] [PMID: 29668503]
[http://dx.doi.org/10.1371/journal.pone.0148001] [PMID: 26808663]
[http://dx.doi.org/10.1016/j.immuni.2018.01.011] [PMID: 29426702]
[http://dx.doi.org/10.1016/j.celrep.2020.107843] [PMID: 32610143]
[http://dx.doi.org/10.1126/science.1110647] [PMID: 15831717]
[http://dx.doi.org/10.1038/nn.3358] [PMID: 23525041]
[http://dx.doi.org/10.1017/S1740925X12000087] [PMID: 22613083]
[http://dx.doi.org/10.1146/annurev-immunol-032713-120240] [PMID: 24471431]
[http://dx.doi.org/10.1002/glia.20896] [PMID: 19544386]
[http://dx.doi.org/10.1084/jem.20041611] [PMID: 15728241]
[http://dx.doi.org/10.1523/JNEUROSCI.4363-08.2009] [PMID: 19339593]
[http://dx.doi.org/10.1126/science.1202529] [PMID: 21778362]
[http://dx.doi.org/10.1002/glia.20711] [PMID: 18512252]
[http://dx.doi.org/10.1523/JNEUROSCI.2251-04.2004] [PMID: 15601948]
[http://dx.doi.org/10.1016/j.bbi.2010.01.007] [PMID: 20116424]
[http://dx.doi.org/10.1371/journal.pone.0060921] [PMID: 23577177]
[http://dx.doi.org/10.1186/s13024-018-0299-8] [PMID: 30541602]
[http://dx.doi.org/10.1016/S1474-4422(15)70016-5] [PMID: 25792098]
[http://dx.doi.org/10.1038/nn2014] [PMID: 18026097]
[PMID: 28317487]
[http://dx.doi.org/10.1016/j.celrep.2018.04.040] [PMID: 29768194]
[http://dx.doi.org/10.1016/j.conb.2020.01.011] [PMID: 32105841]
[http://dx.doi.org/10.1126/science.aay0198] [PMID: 31395777]
[http://dx.doi.org/10.1016/j.brainresbull.2020.01.003] [PMID: 31931120]
[http://dx.doi.org/10.1007/s11064-017-2321-x] [PMID: 28664403]
[http://dx.doi.org/10.1016/j.nbd.2011.01.005] [PMID: 21220023]
[http://dx.doi.org/10.1002/jcp.27659] [PMID: 30417362]
[http://dx.doi.org/10.1002/glia.23782] [PMID: 31922322]
[http://dx.doi.org/10.1016/j.neurobiolaging.2005.09.036] [PMID: 16260066]
[http://dx.doi.org/10.1146/annurev.bi.63.070194.003125] [PMID: 7979249]
[http://dx.doi.org/10.1016/j.jneuroim.2012.06.004] [PMID: 22743055]
[http://dx.doi.org/10.1007/s12640-011-9306-3] [PMID: 22237943]
[http://dx.doi.org/10.1084/jem.20021546] [PMID: 12796468]
[http://dx.doi.org/10.1016/j.freeradbiomed.2004.01.007] [PMID: 15059642]
[http://dx.doi.org/10.1038/ni.1836] [PMID: 20037584]
[http://dx.doi.org/10.3233/JAD-2009-0972] [PMID: 19387110]
[http://dx.doi.org/10.1523/JNEUROSCI.2127-10.2010] [PMID: 20739563]
[http://dx.doi.org/10.1096/fj.09-139634] [PMID: 19906677]
[http://dx.doi.org/10.7717/peerj.8218] [PMID: 31871840]
[http://dx.doi.org/10.1038/s41388-020-1169-8] [PMID: 32020055]
[http://dx.doi.org/10.1007/s12017-009-8085-y] [PMID: 19763906]
[http://dx.doi.org/10.1111/j.1471-4159.2010.06595.x] [PMID: 20132482]
[http://dx.doi.org/10.4049/jimmunol.0901005] [PMID: 19561098]
[http://dx.doi.org/10.1038/ng.803] [PMID: 21460840]
[http://dx.doi.org/10.21037/atm.2018.04.21] [PMID: 29951491]
[http://dx.doi.org/10.1038/nri3737] [PMID: 25234143]
[http://dx.doi.org/10.1002/eji.200425273] [PMID: 15597323]
[http://dx.doi.org/10.1038/nri3233] [PMID: 22699833]
[http://dx.doi.org/10.1002/glia.22992] [PMID: 27121595]
[http://dx.doi.org/10.1152/ajpcell.2001.280.4.C796] [PMID: 11245596]
[http://dx.doi.org/10.1113/jphysiol.2004.070763] [PMID: 15243140]
[http://dx.doi.org/10.1523/JNEUROSCI.3593-06.2007] [PMID: 17202491]
[http://dx.doi.org/10.1016/j.ejphar.2016.11.031] [PMID: 27876619]
[http://dx.doi.org/10.1161/STROKEAHA.114.007445] [PMID: 25477223]
[http://dx.doi.org/10.1007/s11064-017-2223-y] [PMID: 28364331]
[http://dx.doi.org/10.1016/0024-3205(95)00209-O] [PMID: 7623609]
[http://dx.doi.org/10.1016/j.neuropharm.2016.08.003] [PMID: 27511838]
[http://dx.doi.org/10.1002/glia.20432] [PMID: 17024659]
[http://dx.doi.org/10.3233/JAD-170929] [PMID: 29480191]
[http://dx.doi.org/10.4137/IJTR.S13958] [PMID: 24855376]
[http://dx.doi.org/10.2478/v10039-010-0023-6] [PMID: 20639188]
[http://dx.doi.org/10.1371/journal.pone.0059749] [PMID: 23630570]
[http://dx.doi.org/10.1179/174329210X12650506623645] [PMID: 20663292]
[http://dx.doi.org/10.1016/j.jmb.2018.08.002] [PMID: 30098337]
[http://dx.doi.org/10.1016/j.neuropharm.2016.02.030] [PMID: 26924709]
[http://dx.doi.org/10.1002/glia.23001] [PMID: 27219534]
[http://dx.doi.org/10.1124/pr.113.008003] [PMID: 24928329]
[http://dx.doi.org/10.1016/j.psyneuen.2018.08.015] [PMID: 30121550]
[http://dx.doi.org/10.1016/j.jneuroim.2018.11.010] [PMID: 30502599]
[http://dx.doi.org/10.1097/NEN.0000000000000176] [PMID: 25756590]
[http://dx.doi.org/10.1038/s41380-018-0108-3] [PMID: 29934546]
[http://dx.doi.org/10.3389/fphar.2018.00030] [PMID: 29449810]
[http://dx.doi.org/10.1016/j.ejphar.2017.12.006] [PMID: 29225193]
[http://dx.doi.org/10.3858/emm.2011.43.1.001] [PMID: 21088470]
[http://dx.doi.org/10.1016/j.neurobiolaging.2011.09.040] [PMID: 22048123]
[http://dx.doi.org/10.1016/j.neuroscience.2014.08.036] [PMID: 25193238]
[http://dx.doi.org/10.1038/s41583-018-0055-7] [PMID: 30206330]
[http://dx.doi.org/10.1016/j.bbi.2016.12.014] [PMID: 28003153]
[http://dx.doi.org/10.1038/nature25158] [PMID: 29293211]
[http://dx.doi.org/10.1038/ni.2762] [PMID: 24240160]
[http://dx.doi.org/10.1038/nm.4022] [PMID: 26779813]
[http://dx.doi.org/10.1172/JCI58644] [PMID: 22466658]
[http://dx.doi.org/10.1016/j.expneurol.2014.01.001] [PMID: 25017883]
[http://dx.doi.org/10.1016/j.immuni.2017.06.008] [PMID: 28636960]
[http://dx.doi.org/10.1016/j.jns.2011.11.032] [PMID: 22166855]
[http://dx.doi.org/10.1172/JCI96209] [PMID: 29990310]
[http://dx.doi.org/10.1016/j.neurobiolaging.2007.08.018] [PMID: 17905482]
[http://dx.doi.org/10.4049/jimmunol.1101121] [PMID: 22198949]
[http://dx.doi.org/10.1016/j.bbi.2016.07.143] [PMID: 27422717]
[http://dx.doi.org/10.1186/s12974-018-1281-7] [PMID: 30170611]
[http://dx.doi.org/10.1523/JNEUROSCI.1146-08.2008] [PMID: 18509040]
[http://dx.doi.org/10.1093/brain/awl249] [PMID: 16984903]
[http://dx.doi.org/10.1128/CMR.16.4.637-646.2003] [PMID: 14557290]
[http://dx.doi.org/10.1007/s11481-007-9069-z] [PMID: 18040847]
[http://dx.doi.org/10.4049/jimmunol.1600873] [PMID: 27605009]
[http://dx.doi.org/10.1186/1742-2094-9-35] [PMID: 22339795]
[http://dx.doi.org/10.1084/jem.20060136] [PMID: 16717116]
[http://dx.doi.org/10.1016/j.bbi.2016.10.012] [PMID: 27751869]
[http://dx.doi.org/10.1016/j.biopsych.2017.05.014] [PMID: 28666525]
[http://dx.doi.org/10.1056/NEJMoa1211103] [PMID: 23150908]
[http://dx.doi.org/10.1038/ng.3916] [PMID: 28714976]
[http://dx.doi.org/10.1016/j.neuron.2017.02.042] [PMID: 28426958]
[http://dx.doi.org/10.1083/jcb.200808080] [PMID: 19171755]
[http://dx.doi.org/10.3389/fncel.2013.00006] [PMID: 23386811]
[http://dx.doi.org/10.1016/j.neuron.2016.05.003] [PMID: 27196974]
[http://dx.doi.org/10.1186/s13024-018-0247-7] [PMID: 29587871]
[http://dx.doi.org/10.1016/j.jmb.2017.04.004] [PMID: 28432014]
[http://dx.doi.org/10.1038/s41577-018-0051-1] [PMID: 30140051]
[http://dx.doi.org/10.1074/jbc.RA118.002352] [PMID: 29794134]
[http://dx.doi.org/10.7554/eLife.20391] [PMID: 27995897]
[http://dx.doi.org/10.1016/bs.ai.2018.04.002] [PMID: 30249333]
[http://dx.doi.org/10.1016/j.neuron.2017.04.043] [PMID: 28521131]
[http://dx.doi.org/10.1074/jbc.RA118.001848] [PMID: 29599291]