Abstract
Alzheimer Disease (AD) is the most prevalent type of dementia. Pathological changes in the AD brain include Amyloid β-protein (Aβ) plaques and Neurofibrillary Tangles (NFTs), as well as extensive neuronal and synaptic loss. Matrix Metalloproteinase-2 (MMP-2) is a neutral, zinc-dependent protease that primarily targets extracellular matrix proteins. MMP-2 activity is strictly controlled, and its dysregulation has been implicated in a variety of pathologies, including AD. In this brief review, we discussed the contributions of dysregulated MMP-2 activity and an imbalanced interaction between MMP-2 and its endogenous inhibitor, Tissue Inhibitors of Metalloproteinase-2 (TIMP-2), to AD. We also described the underlying mechanisms of the effects of MMP-2/TIMP-2, both beneficial and detrimental, on AD, including: (1) MMP-2 directly degrades Aβ resulting in the clearance of Aβ deposits. Conversely, Aβ-induced MMP-2 may contribute to brain parenchymal destruction. (2) MMP-2 induces breakdown of BBB, and this deleterious effect could be reversed by TIMP-2. (3) MMP-2 disrupts oxidative homeostasis in AD. (4) MMP-2 has both proinflammatory/pro-angiogenetic and antiinflammatory/ anti-angiogenetic effects on AD. Besides, we discuss the clinical utility of MMP- 2/TIMP-2 as therapeutic targets for AD.
Keywords: Matrix metalloproteinase-2, tissue inhibitor of metalloproteinases-2, Alzheimer disease, blood-brain barrier, neuroinflammation, oxidative stress.
Graphical Abstract
[http://dx.doi.org/10.1097/00002093-200210000-00001 ] [PMID: 12468894]
[http://dx.doi.org/10.1007/s10528-009-9275-x] [PMID: 19639408]
[http://dx.doi.org/10.1007/s00726-010-0689-x] [PMID: 20640864]
[http://dx.doi.org/10.1161/01.RES.0000070112.80711.3D ] [PMID: 12730128]
[http://dx.doi.org/10.1016/j.cardiores.2005.12.002] [PMID: 16405877]
[http://dx.doi.org/10.1091/mbc.11.7.2387] [PMID: 10888676]
[http://dx.doi.org/10.1161/hq0701.093685] [PMID: 11451738]
[http://dx.doi.org/10.1016/S1474-4422(09)70016-X ] [PMID: 19161911]
[http://dx.doi.org/10.1016/j.yexcr.2004.03.041] [PMID: 15212943]
[http://dx.doi.org/10.1016/j.bbamcr.2009.04.003] [PMID: 19374923]
[http://dx.doi.org/10.1111/j.1582-4934.2005.tb00355.x ] [PMID: 15963249]
[http://dx.doi.org/10.1016/j.mcn.2015.03.015] [PMID: 25827096]
[http://dx.doi.org/10.1523/JNEUROSCI.22-23-10408.2002 ] [PMID: 12451140]
[http://dx.doi.org/10.1523/JNEUROSCI.1880-05.2006 ] [PMID: 16495447]
[http://dx.doi.org/10.1038/nrm2125] [PMID: 17318226]
[http://dx.doi.org/10.1177/002215540205000304] [PMID: 11850435]
[http://dx.doi.org/10.1177/1073858409355830] [PMID: 20400713]
[http://dx.doi.org/10.1016/j.brainres.2007.10.052] [PMID: 18031717]
[http://dx.doi.org/10.1111/j.1464-5491.2008.02414.x ] [PMID: 18387077]
[http://dx.doi.org/10.1016/j.ijpharm.2019.118625] [PMID: 31425817]
[http://dx.doi.org/10.1016/j.semcdb.2007.06.003] [PMID: 17646116]
[http://dx.doi.org/10.2741/1810] [PMID: 16146744]
[http://dx.doi.org/10.1155/2015/620581] [PMID: 26538832]
[PMID: 2834383]
[http://dx.doi.org/10.1002/glia.20689] [PMID: 18449943]
[http://dx.doi.org/10.1002/cne.20375] [PMID: 15593342]
[http://dx.doi.org/10.3233/JAD-142460] [PMID: 26402409]
[http://dx.doi.org/10.1016/S0167-4838(99)00279-4 ] [PMID: 10708863]
[PMID: 2793861]
[http://dx.doi.org/10.1074/jbc.M001271200] [PMID: 10827176]
[http://dx.doi.org/10.1074/jbc.273.2.871] [PMID: 9422744]
[http://dx.doi.org/10.1002/jcp.20065] [PMID: 15137053]
[http://dx.doi.org/10.1016/j.biochi.2004.07.012] [PMID: 15781320]
[http://dx.doi.org/10.1074/jbc.M603331200] [PMID: 16825197]
[http://dx.doi.org/10.1042/bj20030557] [PMID: 12755684]
[http://dx.doi.org/10.1016/j.pneurobio.2013.03.004 ] [PMID: 23567503]
[http://dx.doi.org/10.1016/S0022-510X(02)00398-2 ] [PMID: 12614934]
[http://dx.doi.org/10.1126/scisignal.127re6] [PMID: 18612141]
[http://dx.doi.org/10.1007/s11033-014-3752-y] [PMID: 25374425]
[http://dx.doi.org/10.1016/j.cell.2005.02.008] [PMID: 15734686]
[http://dx.doi.org/10.1126/science.1072994] [PMID: 12130773]
[http://dx.doi.org/10.1016/S0092-8674(00)80748-5 ] [PMID: 10319819]
[http://dx.doi.org/10.1016/S0196-9781(02)00063-3 ] [PMID: 12128085]
[http://dx.doi.org/10.1042/BST0350416] [PMID: 17371289]
[http://dx.doi.org/10.1038/nrn2168] [PMID: 17551515]
[http://dx.doi.org/10.2147/MNM.S68849]
[http://dx.doi.org/10.1152/physrev.2001.81.2.741] [PMID: 11274343]
[http://dx.doi.org/10.1046/j.1440-1789.2000.00268.x ] [PMID: 10935432]
[http://dx.doi.org/10.2174/092986707782360060] [PMID: 18045131]
[http://dx.doi.org/10.1016/S0169-409X(02)00149-7 ] [PMID: 12453671]
[http://dx.doi.org/10.1038/nature14864] [PMID: 26322584]
[http://dx.doi.org/10.1186/s12974-016-0633-4] [PMID: 27349644]
[http://dx.doi.org/10.1007/s00018-015-1992-1] [PMID: 26202697]
[http://dx.doi.org/10.1186/s40478-014-0135-5] [PMID: 25231068]
[http://dx.doi.org/10.1016/j.bcp.2012.11.014] [PMID: 23178653]
[http://dx.doi.org/10.15252/emmm.201606210] [PMID: 27025652]
[http://dx.doi.org/10.1111/j.1582-4934.2009.00609.x ] [PMID: 19374683]
[http://dx.doi.org/10.1111/j.1750-3639.2008.00132.x ] [PMID: 18363935]
[http://dx.doi.org/10.1074/jbc.M602487200] [PMID: 16648635]
[http://dx.doi.org/10.1016/S0006-8993(03)02344-8 ] [PMID: 12706262]
[http://dx.doi.org/10.3389/fnagi.2014.00247] [PMID: 25278878]
[http://dx.doi.org/10.1523/JNEUROSCI.2085-06.2006 ] [PMID: 17065436]
[http://dx.doi.org/10.1074/jbc.M114.610931] [PMID: 25897080]
[http://dx.doi.org/10.1111/j.1471-4159.2009.05870.x ] [PMID: 19141082]
[http://dx.doi.org/10.1074/jbc.M602440200] [PMID: 16787929]
[http://dx.doi.org/10.1155/2017/4810232] [PMID: 28197357]
[http://dx.doi.org/10.1038/nrm2101] [PMID: 17245412]
[http://dx.doi.org/10.1016/j.brainres.2011.02.078] [PMID: 21376707]
[http://dx.doi.org/10.1042/BST0380955] [PMID: 20658984]
[http://dx.doi.org/10.1042/BST0381016] [PMID: 20658996]
[http://dx.doi.org/10.2174/156720510793611600] [PMID: 20678070]
[http://dx.doi.org/10.3390/ijms19040956] [PMID: 29570615]
[http://dx.doi.org/10.1126/science.1113694] [PMID: 16020737]
[http://dx.doi.org/10.1016/j.bbamcr.2017.05.013] [PMID: 28526562]
[http://dx.doi.org/10.1038/nrn1824] [PMID: 16371949]
[http://dx.doi.org/10.1016/j.nbd.2009.07.030] [PMID: 19664713]
[http://dx.doi.org/10.1101/cshperspect.a020412] [PMID: 25561720]
[http://dx.doi.org/10.1078/0171-9335-00101] [PMID: 11089919]
[http://dx.doi.org/10.1387/ijdb.103224sl] [PMID: 21769778]
[http://dx.doi.org/10.4161/tisb.23993] [PMID: 24665385]
[PMID: 27355558]
[http://dx.doi.org/10.1371/journal.pone.0020599] [PMID: 21857898]
[http://dx.doi.org/10.1523/JNEUROSCI.6409-11.2012 ] [PMID: 22378877]
[http://dx.doi.org/10.1016/j.neuroscience.2018.02.035 ] [PMID: 29524637]
[http://dx.doi.org/10.3389/fncel.2018.00288] [PMID: 30233326]
[http://dx.doi.org/10.1016/j.tox.2011.03.019] [PMID: 21501651]
[http://dx.doi.org/10.1007/s12031-011-9689-x] [PMID: 22173873]
[http://dx.doi.org/10.1172/JCI58644] [PMID: 22466658]
[http://dx.doi.org/10.1371/journal.pone.0041823] [PMID: 22860017]
[http://dx.doi.org/10.1007/s10571-011-9744-8] [PMID: 21837459]
[http://dx.doi.org/10.1155/2017/1809592] [PMID: 28194255]
[http://dx.doi.org/10.1007/s12035-015-9337-5] [PMID: 26198567]
[http://dx.doi.org/10.1016/j.neurobiolaging.2005.01.001 ] [PMID: 16399211]
[http://dx.doi.org/10.1016/j.pathophys.2006.05.004 ] [PMID: 16781128]
[http://dx.doi.org/10.1155/2014/182303] [PMID: 24949424]
[http://dx.doi.org/10.1016/j.redox.2017.10.014 ] [PMID: 29080524]
[http://dx.doi.org/10.1111/j.1471-4159.2006.04393.x ] [PMID: 17250680]
[http://dx.doi.org/10.1097/00004647-200112000-00003 ] [PMID: 11740200]
[PMID: 19273096]
[http://dx.doi.org/10.1016/j.bcp.2008.11.004] [PMID: 19046943]
[http://dx.doi.org/10.1016/j.bbagen.2004.01.005] [PMID: 15026147]
[http://dx.doi.org/10.1074/jbc.M202647200] [PMID: 12058032]
[http://dx.doi.org/10.1016/j.freeradbiomed.2009.02.011 ] [PMID: 19248829]
[http://dx.doi.org/10.1111/j.1471-4159.2009.06096.x ] [PMID: 19457117]
[http://dx.doi.org/10.1007/s11010-013-1848-7] [PMID: 24114660]
[http://dx.doi.org/10.1007/s12012-013-9231-1 ] [PMID: 24104944]
[http://dx.doi.org/10.2147/DDDT.S187842] [PMID: 31213768]
[http://dx.doi.org/10.2147/NDT.S75546] [PMID: 25673992]
[http://dx.doi.org/10.1007/s00702-010-0438-z] [PMID: 20632195]
[http://dx.doi.org/10.1523/JNEUROSCI.20-02-00558.2000 ] [PMID: 10632585]
[http://dx.doi.org/10.1007/s00018-019-03171-9] [PMID: 31165203]
[http://dx.doi.org/10.3390/cells8090984] [PMID: 31461880]
[http://dx.doi.org/10.2741/2161] [PMID: 17127395]
[PMID: 10652271]
[http://dx.doi.org/10.1038/nri1418] [PMID: 15286728]
[http://dx.doi.org/10.1111/j.0906-6713.2004.003569.x ] [PMID: 15107057]
[http://dx.doi.org/10.1074/jbc.275.19.14046] [PMID: 10799478]
[http://dx.doi.org/10.1080/10409230701340019] [PMID: 17562450]
[http://dx.doi.org/10.1186/1742-2094-11-116] [PMID: 24970341]
[http://dx.doi.org/10.1038/nri3499] [PMID: 23969736]
[http://dx.doi.org/10.1126/science.289.5482.1202] [PMID: 10947989]
[http://dx.doi.org/10.1182/blood.V100.4.1160.h81602001160_1160_1167] [PMID: 12149192]
[http://dx.doi.org/10.4049/jimmunol.1202286] [PMID: 23225890]
[http://dx.doi.org/10.1189/jlb.0607338] [PMID: 17709402]
[http://dx.doi.org/10.1021/ol0517269] [PMID: 16178559]
[http://dx.doi.org/10.1371/journal.pone.0076904] [PMID: 24194849]
[http://dx.doi.org/10.1177/1479164111427753] [PMID: 22045867]
[http://dx.doi.org/10.1016/j.tips.2013.02.004] [PMID: 23541335]
[http://dx.doi.org/10.1016/j.tins.2005.02.001] [PMID: 15808355]
[http://dx.doi.org/10.1074/jbc.M307907200] [PMID: 14576162]
[http://dx.doi.org/10.1186/alzrt230] [PMID: 24351529]
[http://dx.doi.org/10.1016/S0093-7754(02)70065-1 ] [PMID: 12516034]
[PMID: 12956462]
[http://dx.doi.org/10.1016/S1357-2725(01)00007-3 ] [PMID: 11470230]
[http://dx.doi.org/10.1016/j.ceb.2004.07.010] [PMID: 15363807]
[http://dx.doi.org/10.1074/jbc.M107736200] [PMID: 11571304]
[http://dx.doi.org/10.1002/ijc.25134] [PMID: 20027628]
[http://dx.doi.org/10.1016/j.mvr.2008.07.003] [PMID: 18721821]
[http://dx.doi.org/10.1158/0008-5472.CAN-04-1981 ] [PMID: 15604273]
[http://dx.doi.org/10.1016/S0092-8674(01)00597-9 ] [PMID: 11747814]
[http://dx.doi.org/10.1097/00062752-200303000-00007 ] [PMID: 12579040]
[http://dx.doi.org/10.1016/S0002-9440(10)64887-0 ] [PMID: 11839588]
[http://dx.doi.org/10.1002/ijc.21645] [PMID: 16381009]
[http://dx.doi.org/10.3233/JAD-131634] [PMID: 24448781]
[http://dx.doi.org/10.1016/j.molmed.2005.01.007] [PMID: 15760767]
[http://dx.doi.org/10.1016/S0092-8674(03)00551-8 ] [PMID: 12887919]
[http://dx.doi.org/10.3233/JAD-2012-120067] [PMID: 22850316]
[http://dx.doi.org/10.2174/1568009054064615] [PMID: 15975049]
[http://dx.doi.org/10.1016/j.tips.2008.11.002] [PMID: 19110321]
[http://dx.doi.org/10.1080/17460441.2018.1398732]
[http://dx.doi.org/10.1038/nrd4390] [PMID: 25376097]
[http://dx.doi.org/10.1016/j.bbamcr.2017.06.009] [PMID: 28636874]
[http://dx.doi.org/10.1074/jbc.M117.818542] [PMID: 29794029]
[http://dx.doi.org/10.1111/bph.14186] [PMID: 29488211]
[http://dx.doi.org/10.1038/nm.2582] [PMID: 22198278]
[http://dx.doi.org/10.1158/0008-5472.CAN-08-3255 ] [PMID: 19208838]
[http://dx.doi.org/10.1074/jbc.M112.447169] [PMID: 23413031]
[http://dx.doi.org/10.1016/j.ceb.2009.06.006] [PMID: 19616423]
[http://dx.doi.org/10.1046/j.1471-4159.2003.01745.x ] [PMID: 12753080]
[http://dx.doi.org/10.1523/JNEUROSCI.0006-15.2015 ] [PMID: 26377465]
[http://dx.doi.org/10.1124/jpet.109.154724] [PMID: 19587312]
[http://dx.doi.org/10.1159/000492573] [PMID: 30196300]
[http://dx.doi.org/10.1038/nm.3569] [PMID: 24793238]
[http://dx.doi.org/10.1001/jamaneurol.2016.3185] [PMID: 27598869]
[http://dx.doi.org/10.1038/nature22067] [PMID: 28424512]
[http://dx.doi.org/10.1016/j.neulet.2009.09.043] [PMID: 19786072]
[http://dx.doi.org/10.1017/S1041610210000827] [PMID: 20561382]
[http://dx.doi.org/10.3233/JAD-130647] [PMID: 23792694]
[http://dx.doi.org/10.1385/JMN:23:1-2:115] [PMID: 15126697]