Abstract
Alzheimer’s Disease (AD) is a common neurodegenerative disorder that is almost incurable with the existing therapeutic interventions. Due to the high-risk factors associated with this disease, there is a global pursuit of new anti-AD agents. Herein, we explore the biochemical pathways which are responsible for the initiation/propagation of the disease. It is observed that out of the two isoforms of β-secretase, β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and β-site amyloid precursor protein cleaving enzyme 2 (BACE2) present in the brain, BACE1 plays the predominant role in the commencement of AD. Moreover, the catalytic activities of acetylcholinesterase and butyrylcholinesterase regulate the concentration of neurotransmitters, and they are needed to be kept under control during the signs of AD. Hence, these two enzymes also serve as potential targets for the treatment of AD patients. Keeping in view the multifactorial nature of the disease, we also reviewed the multitarget approach for the treatment of AD. It is tried to identify the common structural features of those molecules which act on different cellular targets during AD therapy.
Keywords: Multi-factorial disease, biochemistry of alzheimer’s disease, Amyloid precursor protein; beta-site APP cleaving enzyme, neurotransmitters, multi-target inhibitors.
Graphical Abstract
[http://dx.doi.org/10.1016/S0140-6736(20)30367-6] [PMID: 32738937]
[http://dx.doi.org/10.1017/S1092852900014164] [PMID: 16273023]
[http://dx.doi.org/10.1007/s10571-014-0074-5] [PMID: 24927694]
[http://dx.doi.org/10.3390/ijerph16142560] [PMID: 31323750]
[http://dx.doi.org/10.1016/j.neuroscience.2013.04.060] [PMID: 23644052]
[http://dx.doi.org/10.1016/j.cell.2019.09.001] [PMID: 31564456]
[http://dx.doi.org/10.3934/Neuroscience.2021005] [PMID: 33490374]
[PMID: 26203236]
[http://dx.doi.org/10.1146/annurev-neuro-061010-113613] [PMID: 21456963]
[http://dx.doi.org/10.1523/JNEUROSCI.1450-06.2006] [PMID: 16822978]
[http://dx.doi.org/10.1016/S0301-0082(03)00089-3] [PMID: 12927332]
[http://dx.doi.org/10.1371/journal.pone.0009505] [PMID: 20209079]
[http://dx.doi.org/10.1016/j.cell.2010.08.014] [PMID: 20817278]
[http://dx.doi.org/10.1186/1750-1326-6-27] [PMID: 21527012]
[http://dx.doi.org/10.4155/fso.15.9] [PMID: 28031886]
[http://dx.doi.org/10.3233/JAD-2010-1221] [PMID: 20061647]
[http://dx.doi.org/10.1111/j.1471-4159.2009.06528.x] [PMID: 19968762]
[http://dx.doi.org/10.3390/ph12010041] [PMID: 30893882]
[http://dx.doi.org/10.1056/NEJMoa1812840] [PMID: 30970186]
[http://dx.doi.org/10.1021/acs.jmedchem.6b00307] [PMID: 27933948]
[http://dx.doi.org/10.1074/jbc.M112.409110] [PMID: 23048024]
[http://dx.doi.org/10.15252/emmm.201809316] [PMID: 30224383]
[http://dx.doi.org/10.3233/JAD-150834] [PMID: 26890753]
[http://dx.doi.org/10.1001/jamaneurol.2019.3988] [PMID: 31764959]
[http://dx.doi.org/10.1002/cpdd.422] [PMID: 29319935]
[http://dx.doi.org/10.1186/s13195-018-0415-6] [PMID: 30134967]
[http://dx.doi.org/10.1186/s40035-016-0061-5] [PMID: 27418961]
[http://dx.doi.org/10.1186/s13195-020-00614-5] [PMID: 32410694]
[http://dx.doi.org/10.1016/j.bmcl.2014.03.025] [PMID: 24704031]
[http://dx.doi.org/10.1016/j.trci.2019.02.005] [PMID: 31211217]
[http://dx.doi.org/10.1017/S1461145705005833] [PMID: 16083515]
[http://dx.doi.org/10.1002/0470846577.ch6]
[http://dx.doi.org/10.1093/bja/aem144] [PMID: 17573397]
[http://dx.doi.org/10.1016/S0969-2126(99)80040-9] [PMID: 10368299]
[http://dx.doi.org/10.5214/ans.0972.7531.2008.150403]
[http://dx.doi.org/10.1093/emboj/cdg005] [PMID: 12505979]
[http://dx.doi.org/10.1523/JNEUROSCI.1106-04.2004] [PMID: 15201317]
[http://dx.doi.org/10.1016/B978-0-12-815320-8.00016-8]
[http://dx.doi.org/10.1016/j.phrs.2016.12.033] [PMID: 28040533]
[http://dx.doi.org/10.1002/ardp.201800050] [PMID: 29870588]
[http://dx.doi.org/10.1073/pnas.90.19.9031] [PMID: 8415649]
[http://dx.doi.org/10.1021/bi020016x] [PMID: 11888271]
[http://dx.doi.org/10.2147/nedt.2007.3.2.211] [PMID: 19300554]
[http://dx.doi.org/10.1021/jm300871x] [PMID: 23035744]
[http://dx.doi.org/10.1159/000086613] [PMID: 15990426]
[http://dx.doi.org/10.1016/j.clinthera.2008.04.005] [PMID: 18498913]
[http://dx.doi.org/10.3390/nu11112694] [PMID: 31703329]
[http://dx.doi.org/10.1016/j.bioorg.2020.103997] [PMID: 32554280]
[http://dx.doi.org/10.1016/j.bioorg.2018.10.065] [PMID: 30412794]
[http://dx.doi.org/10.1080/14756366.2018.1545766] [PMID: 30712420]
[http://dx.doi.org/10.1016/j.ejmech.2020.112180] [PMID: 32131034]
[http://dx.doi.org/10.1016/j.ejmech.2019.111958] [PMID: 31865014]
[http://dx.doi.org/10.1039/C9MD00441F] [PMID: 33479629]
[http://dx.doi.org/10.1021/jm201460y] [PMID: 22243648]
[http://dx.doi.org/10.3390/ijms20215451] [PMID: 31683761]
[http://dx.doi.org/10.1016/j.bmc.2016.11.048] [PMID: 27923535]
[http://dx.doi.org/10.1002/ddr.21544] [PMID: 31050027]
[http://dx.doi.org/10.3390/molecules23123252] [PMID: 30544832]
[http://dx.doi.org/10.1016/j.ejmech.2021.113783] [PMID: 34461507]
[http://dx.doi.org/10.1016/j.ejmech.2018.10.064] [PMID: 30447434]
[http://dx.doi.org/10.1080/14756366.2019.1699553] [PMID: 31856607]
[http://dx.doi.org/10.1021/acs.jmedchem.0c00528] [PMID: 32706255]
[http://dx.doi.org/10.1016/j.ejmech.2017.12.005] [PMID: 29268129]
[http://dx.doi.org/10.1021/acs.jmedchem.1c00160] [PMID: 34024109]
[http://dx.doi.org/10.1016/j.bmc.2020.115721] [PMID: 33007563]
[http://dx.doi.org/10.1073/pnas.1410315111] [PMID: 25157130]
[http://dx.doi.org/10.1021/acschemneuro.8b00699] [PMID: 30720268]
[http://dx.doi.org/10.3390/biom11010111] [PMID: 33467709]
[http://dx.doi.org/10.1016/j.ejmech.2021.113973] [PMID: 34752955]
[http://dx.doi.org/10.1016/j.bioorg.2020.104201] [PMID: 32890999]
[http://dx.doi.org/10.1016/j.bmcl.2016.03.086] [PMID: 27072909]
[http://dx.doi.org/10.1016/j.ejmech.2020.112265] [PMID: 32240904]
[http://dx.doi.org/10.1016/j.bmcl.2020.127505] [PMID: 32822761]
[http://dx.doi.org/10.1021/jm3009458] [PMID: 23033965]
[http://dx.doi.org/10.1038/srep33172] [PMID: 27609215]
[http://dx.doi.org/10.1021/acs.molpharmaceut.9b00252] [PMID: 31241959]
[http://dx.doi.org/10.1002/ange.201410456]
[http://dx.doi.org/10.1038/s41467-021-21330-0] [PMID: 33589615]