Abstract
Alzheimer's disease (AD) is a multifactorial, progressive, neurodegenerative disorder, manifested by the loss of memory and cognitive abilities, behavioral disturbance and progressive impairment of activities of daily life. The sharp rise in the number of AD patients has brought it within the top eight health issues in the world. It is associated with the distribution of misfolded aggregates of protein within the brain. However, Alois Alzheimer initially mentioned that the reduction in brain volume in AD might be associated with the “deposition of a special substance in the cortex”. The resulting plaque found in extracellular space in the AD brain and hippocampus region, known as senile plaques, is the characteristic feature underlying Alzheimer’s pathology, where the role of amyloid- β (Aβ) peptide formation from proteolytic cleavage of amyloid precursor protein (APP) by secretase enzyme is eminent. Therefore, this review has highlighted the molecular pathophysiology of AD with a variety of available diagnostic and treatment strategies for the management of the disease, with a focus on the advancement toward clinical research to provide new effective and safe tool in the diagnosis, treatment or management of AD.
Keywords: Alzheimer’s disease, neuroimaging, neurodegenerative, secretase enzyme, biomarker, amyloid precursor protein.
Graphical Abstract
[http://dx.doi.org/10.1007/s40263-019-00695-3] [PMID: 31933283]
[http://dx.doi.org/10.1097/01.wco.0000227033.47458.82] [PMID: 16702830]
[http://dx.doi.org/10.1016/j.progpolymsci.2014.12.002]
[http://dx.doi.org/10.1016/j.progpolymsci.2007.05.014] [PMID: 20234846]
[http://dx.doi.org/10.1086/503565] [PMID: 16619159]
[http://dx.doi.org/10.1038/s41582-020-0333-7] [PMID: 32203399]
[http://dx.doi.org/10.1002/ana.22615] [PMID: 22028219]
[http://dx.doi.org/10.1016/j.intimp.2020.106417] [PMID: 32200155]
[http://dx.doi.org/10.1016/j.drudis.2019.11.003] [PMID: 31738877]
[http://dx.doi.org/10.1152/physrev.00050.2017] [PMID: 30280653]
[http://dx.doi.org/10.1080/13550280290168631] [PMID: 12476342]
[http://dx.doi.org/10.1016/j.jcis.2016.07.047] [PMID: 27501037]
[http://dx.doi.org/10.2174/1567201814666171120125916] [PMID: 29165080]
[http://dx.doi.org/10.1016/j.drudis.2014.09.019] [PMID: 25281591]
[http://dx.doi.org/10.1016/S0140-6736(10)61349-9] [PMID: 21371747]
[http://dx.doi.org/10.1016/S0140-6736(05)67889-0] [PMID: 16360788]
[http://dx.doi.org/10.1016/j.progpolymsci.2016.09.006]
[http://dx.doi.org/10.1039/C6RA17290C]
[http://dx.doi.org/10.1016/j.jconrel.2020.07.044] [PMID: 32739524]
[http://dx.doi.org/10.1016/j.ijpharm.2019.05.032] [PMID: 31095983]
[http://dx.doi.org/10.2174/1381612826666200313125613] [PMID: 32167424]
[http://dx.doi.org/10.1016/j.jddst.2017.09.022]
[http://dx.doi.org/10.1016/j.ijpharm.2021.120351] [PMID: 33545286]
[http://dx.doi.org/10.1007/s13346-018-0552-2] [PMID: 29916012]
[http://dx.doi.org/10.1016/j.drudis.2016.02.006] [PMID: 26891979]
[http://dx.doi.org/10.1016/j.jconrel.2021.10.028] [PMID: 34757195]
[http://dx.doi.org/10.1080/09205063.2015.1133155] [PMID: 26928261]
[http://dx.doi.org/10.1080/13543784.2019.1627325] [PMID: 31155971]
[http://dx.doi.org/10.1016/B978-0-12-812218-1.00014-2]
[http://dx.doi.org/10.1016/j.neulet.2021.135865] [PMID: 33812929]
[http://dx.doi.org/10.1016/B978-0-12-820466-5.00008-9]
[http://dx.doi.org/10.1602/neurorx.2.1.3] [PMID: 15717053]
[http://dx.doi.org/10.1016/j.progpolymsci.2013.07.005]
[http://dx.doi.org/10.1016/B978-0-12-812218-1.00010-5]
[http://dx.doi.org/10.1016/j.jddst.2019.02.013]
[http://dx.doi.org/10.31887/DCNS.2003.5.1/hhippius] [PMID: 22034141]
[http://dx.doi.org/10.1016/j.pharep.2015.07.006] [PMID: 26721364]
[http://dx.doi.org/10.1146/annurev-publhealth-040218-043758] [PMID: 30642228]
[http://dx.doi.org/10.1002/alz.12068]
[http://dx.doi.org/10.1096/fj.201900723RRR] [PMID: 31914623]
[http://dx.doi.org/10.1007/s12035-019-1540-3] [PMID: 30852796]
[http://dx.doi.org/10.1186/s12888-018-1910-9] [PMID: 30290789]
[http://dx.doi.org/10.1111/bpa.12812] [PMID: 31912564]
[http://dx.doi.org/10.3233/JAD-160763] [PMID: 27662322]
[http://dx.doi.org/10.1146/annurev.biochem.75.103004.142637] [PMID: 16756504]
[http://dx.doi.org/10.1007/BF03160024] [PMID: 8466596]
[http://dx.doi.org/10.1038/nrn2494] [PMID: 18802446]
[http://dx.doi.org/10.1016/j.neuron.2010.09.043] [PMID: 21040844]
[http://dx.doi.org/10.1016/S0006-291X(84)80190-4] [PMID: 6375662]
[http://dx.doi.org/10.1177/1533317508328602] [PMID: 19116299]
[http://dx.doi.org/10.1126/science.1255555] [PMID: 26250687]
[http://dx.doi.org/10.1002/anie.200802808] [PMID: 19330877]
[http://dx.doi.org/10.1002/jnr.10737] [PMID: 14598310]
[http://dx.doi.org/10.1126/science.286.5440.735] [PMID: 10531052]
[http://dx.doi.org/10.1007/0-387-23226-5_5]
[http://dx.doi.org/10.1016/S0021-9258(18)53650-4] [PMID: 8428976]
[http://dx.doi.org/10.1046/j.1365-2559.2001.01082.x] [PMID: 11207825]
[http://dx.doi.org/10.1074/jbc.270.40.23243] [PMID: 7559474]
[http://dx.doi.org/10.1038/nrn2168] [PMID: 17551515]
[http://dx.doi.org/10.1016/S0306-4522(01)00460-2] [PMID: 11958863]
[http://dx.doi.org/10.1096/fj.05-3735fje] [PMID: 16210396]
[http://dx.doi.org/10.1016/S0165-0173(00)00019-9] [PMID: 10967355]
[http://dx.doi.org/10.1038/nrn2194] [PMID: 17684513]
[http://dx.doi.org/10.1083/jcb.200106025] [PMID: 11581286]
[http://dx.doi.org/10.1016/S0021-9258(20)80536-5] [PMID: 8226987]
[http://dx.doi.org/10.1073/pnas.91.12.5562] [PMID: 8202528]
[http://dx.doi.org/10.1002/clc.4960290313] [PMID: 16596840]
[http://dx.doi.org/10.3389/fncel.2013.00252] [PMID: 24376398]
[http://dx.doi.org/10.1097/00005072-199808000-00001] [PMID: 9720487]
[http://dx.doi.org/10.1358/dot.2004.40.8.850473] [PMID: 15510242]
[http://dx.doi.org/10.2174/9781681085609118070009]
[http://dx.doi.org/10.1016/j.bmc.2011.05.027] [PMID: 22172310]
[http://dx.doi.org/10.1002/cne.23415] [PMID: 23852922]
[http://dx.doi.org/10.1007/s12272-013-0036-3] [PMID: 23435942]
[http://dx.doi.org/10.1016/0197-4580(83)90038-6] [PMID: 6355883]
[http://dx.doi.org/10.1016/j.tips.2015.03.002] [PMID: 25840462]
[http://dx.doi.org/10.1126/science.1072994] [PMID: 12130773]
[http://dx.doi.org/10.1016/S0197-0186(99)00125-4] [PMID: 10676850]
[http://dx.doi.org/10.1136/jnnp.57.4.419] [PMID: 8163989]
[http://dx.doi.org/10.1097/GIM.0b013e31816b64dc] [PMID: 18414205]
[http://dx.doi.org/10.1016/0165-6147(91)90609-V] [PMID: 1763432]
[http://dx.doi.org/10.1038/360672a0] [PMID: 1465129]
[http://dx.doi.org/10.1016/j.febslet.2004.06.025] [PMID: 15251450]
[http://dx.doi.org/10.1080/13813450701572288] [PMID: 17922309]
[http://dx.doi.org/10.1038/nm0896-864] [PMID: 8705854]
[http://dx.doi.org/10.1038/325733a0] [PMID: 2881207]
[http://dx.doi.org/10.1016/S1474-4422(20)30412-9] [PMID: 33340485]
[http://dx.doi.org/10.1016/j.neuron.2018.12.036] [PMID: 30685224]
[http://dx.doi.org/10.4172/2161-0460.1000443]
[http://dx.doi.org/10.1016/j.npep.2015.06.008] [PMID: 26149638]
[http://dx.doi.org/10.1038/nrd2111] [PMID: 17541419]
[http://dx.doi.org/10.1016/j.jalz.2006.07.001] [PMID: 19595897]
[http://dx.doi.org/10.1016/j.neurobiolaging.2006.06.021] [PMID: 16876913]
[http://dx.doi.org/10.1093/ageing/23.5.396] [PMID: 7825486]
[http://dx.doi.org/10.1159/000054469] [PMID: 10461029]
[http://dx.doi.org/10.1212/WNL.50.1.164] [PMID: 9443474]
[http://dx.doi.org/10.1093/oxfordjournals.aje.a009106] [PMID: 9054233]
[http://dx.doi.org/10.1212/WNL.53.9.1937] [PMID: 10599761]
[http://dx.doi.org/10.2165/00023210-200317010-00003] [PMID: 12467491]
[http://dx.doi.org/10.1016/j.neurobiolaging.2008.07.021] [PMID: 18771816]
[http://dx.doi.org/10.1097/00001756-199301000-00018] [PMID: 8453039]
[http://dx.doi.org/10.1212/01.wnl.0000311269.57716.63] [PMID: 18458226]
[http://dx.doi.org/10.1007/s12035-014-8657-1] [PMID: 24567119]
[http://dx.doi.org/10.1016/j.jneuroim.2014.06.026] [PMID: 25037175]
[http://dx.doi.org/10.1016/j.biopsych.2014.05.006] [PMID: 24951455]
[http://dx.doi.org/10.1002/path.1711670403] [PMID: 1328575]
[http://dx.doi.org/10.1016/j.neuron.2018.05.023] [PMID: 29937276]
[http://dx.doi.org/10.1016/j.cell.2019.09.001] [PMID: 31564456]
[http://dx.doi.org/10.1016/j.cell.2013.03.030] [PMID: 23622250]
[http://dx.doi.org/10.1038/s41467-018-08279-3] [PMID: 30679421]
[http://dx.doi.org/10.1016/0197-4580(91)90006-6] [PMID: 1961359]
[http://dx.doi.org/10.1016/S0021-9258(19)41496-8] [PMID: 236308]
[http://dx.doi.org/10.1161/01.STR.0000058480.77236.B3] [PMID: 12624314]
[http://dx.doi.org/10.1038/nm890] [PMID: 12808450]
[http://dx.doi.org/10.1016/j.ijpharm.2019.05.042] [PMID: 31102804]
[http://dx.doi.org/10.1038/325253a0] [PMID: 3543687]
[http://dx.doi.org/10.1016/0169-409X(96)00011-7]
[http://dx.doi.org/10.2174/2211556007666180420124544]
[http://dx.doi.org/10.1016/S0896-6273(01)00475-5] [PMID: 11683988]
[http://dx.doi.org/10.1038/382685a0] [PMID: 8751438]
[http://dx.doi.org/10.1377/hlthaff.2013.1353] [PMID: 24711318]
[http://dx.doi.org/10.1016/j.jsbmb.2016.03.012] [PMID: 26969397]
[http://dx.doi.org/10.5114/fn.2014.45562] [PMID: 25310732]
[http://dx.doi.org/10.1016/S0140-6736(17)31363-6] [PMID: 28735855]
[http://dx.doi.org/10.1016/j.phrs.2018.04.017] [PMID: 29689315]
[http://dx.doi.org/10.1016/j.jalz.2015.05.016] [PMID: 26045020]
[http://dx.doi.org/10.1186/s12916-014-0130-5] [PMID: 25385322]
[http://dx.doi.org/10.1007/s11886-012-0304-8] [PMID: 22968344]
[http://dx.doi.org/10.1016/j.neuron.2013.10.008] [PMID: 24267647]
[http://dx.doi.org/10.5114/fn.2019.85929] [PMID: 31556570]
[http://dx.doi.org/10.1016/j.ncl.2017.01.006] [PMID: 28410660]
[http://dx.doi.org/10.1136/jnnp-2015-310548] [PMID: 26294005]
[http://dx.doi.org/10.1016/j.biocel.2012.07.019] [PMID: 22842534]
[http://dx.doi.org/10.1016/j.biocel.2012.07.019] [PMID: 22842534]
[http://dx.doi.org/10.1093/toxsci/kfu208] [PMID: 25288670]
[http://dx.doi.org/10.1007/978-1-4939-7674-4_2]
[http://dx.doi.org/10.1002/cne.20840] [PMID: 16432899]
[http://dx.doi.org/10.1523/JNEUROSCI.0884-19.2019] [PMID: 31217332]
[http://dx.doi.org/10.3233/JAD-179920]
[http://dx.doi.org/10.1101/cshperspect.a006213] [PMID: 22474610]
[http://dx.doi.org/10.1017/S0317167100037276] [PMID: 3791069]
[http://dx.doi.org/10.1016/0165-1781(84)90060-X] [PMID: 6596584]
[http://dx.doi.org/10.1111/jnc.13212] [PMID: 26118667]
[http://dx.doi.org/10.1128/AAC.02097-16]
[http://dx.doi.org/10.1016/j.neuroscience.2017.07.017] [PMID: 28729061]
[http://dx.doi.org/10.1242/dmm.031781] [PMID: 29739861]
[http://dx.doi.org/10.1097/00000441-193907000-00014]
[http://dx.doi.org/10.1097/00000441-193907000-00015]
[http://dx.doi.org/10.1097/00000441-193907000-00013]
[http://dx.doi.org/10.1016/S1474-4422(09)70299-6] [PMID: 20083042]
[http://dx.doi.org/10.4061/2010/606802] [PMID: 20721349]
[http://dx.doi.org/10.1016/j.bcp.2013.12.024] [PMID: 24398425]
[http://dx.doi.org/10.1001/archneurol.2010.179] [PMID: 20697045]
[http://dx.doi.org/10.1186/s13195-020-00596-4] [PMID: 32183883]
[http://dx.doi.org/10.1016/j.jalz.2018.05.006] [PMID: 29936146]
[http://dx.doi.org/10.1016/S1474-4422(16)00070-3] [PMID: 27068280]
[http://dx.doi.org/10.1016/j.neurobiolaging.2007.08.010] [PMID: 17889968]
[http://dx.doi.org/10.1186/s13041-019-0448-1] [PMID: 30922367]
[http://dx.doi.org/10.7860/JCDR/2016/18828.8166]
[http://dx.doi.org/10.3233/JAD-170810] [PMID: 29376870]
[http://dx.doi.org/10.1038/s41582-018-0058-z] [PMID: 30171200]
[http://dx.doi.org/10.3233/JAD-190700] [PMID: 31524172]
[http://dx.doi.org/10.3233/JAD-181088] [PMID: 30909232]
[http://dx.doi.org/10.2147/CBF.S46067]
[http://dx.doi.org/10.1155/2019/6216530] [PMID: 30863455]
[http://dx.doi.org/10.1016/S1474-4422(17)30083-2] [PMID: 28460892]
[http://dx.doi.org/10.1016/j.neulet.2019.134355] [PMID: 31260726]
[http://dx.doi.org/10.1016/j.bionps.2019.100005]
[http://dx.doi.org/10.2174/1570159X13666150716165726] [PMID: 26813123]
[http://dx.doi.org/10.3389/fnins.2019.00446] [PMID: 31133787]
[PMID: 22500154]
[PMID: 31257471]
[http://dx.doi.org/10.1212/WNL.50.1.136] [PMID: 9443470]
[http://dx.doi.org/10.1155/2012/728983] [PMID: 22216416]
[http://dx.doi.org/10.1111/j.1527-3458.2002.tb00221.x] [PMID: 12177686]
[http://dx.doi.org/10.1021/cr040415t] [PMID: 16402773]
[http://dx.doi.org/10.1007/BF00783088]
[http://dx.doi.org/10.1586/14737175.8.1.9] [PMID: 18088197]
[http://dx.doi.org/10.1080/14740338.2020.1721456] [PMID: 31976781]
[http://dx.doi.org/10.2147/NDT.S4048] [PMID: 19557118]
[http://dx.doi.org/10.3233/JAD-170424] [PMID: 28922160]
[http://dx.doi.org/10.1523/JNEUROSCI.2506-07.2007] [PMID: 17855613]
[PMID: 30891742]
[http://dx.doi.org/10.1016/j.cbi.2006.06.002] [PMID: 16860785]
[http://dx.doi.org/10.2174/092986710791111206] [PMID: 20345341]
[PMID: 17636619]
[http://dx.doi.org/10.2174/15680266113139990136] [PMID: 23931443]
[http://dx.doi.org/10.1126/science.1566067] [PMID: 1566067]
[http://dx.doi.org/10.1002/alz.12213] [PMID: 33135381]
[http://dx.doi.org/10.1016/j.phrs.2021.105754] [PMID: 34217830]
[http://dx.doi.org/10.1038/s41392-019-0063-8]