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2000
Volume 31, Issue 17
  • ISSN: 1381-6128
  • E-ISSN: 1873-4286

Abstract

Alzheimer's disease (AD) is a gradual degenerative ailment of the nervous system that is marked by the buildup of amyloid-β plaques and neurofibrillary tangles. This accumulation causes problems with the connections between nerve cells and the loss of these cells. This review paper explores the complex pathophysiology of AD, analyzing the neuronal loss reported in key brain regions like the entorhinal cortex, amygdala, hippocampus, and cortical association areas. The text also examines subcortical nuclei participation, such as the noradrenergic locus coeruleus, serotonergic dorsal raphe, and cholinergic basal nucleus. Also, this review discusses the importance of tau protein hyperphosphorylation, oxidative stress, and metal ion dysregulation in the evolution of AD. Moreover, it explores the cholinergic theory and the influence of the APOE (apolipoprotein E) genotype on the effectiveness of therapy. This article thoroughly summarizes the current knowledge on AD, including its clinical symptoms and possible treatment approaches, by combining several theories and new targets. The study highlights the connection between the degree of tangle development and the severity of dementia, underlining the need for creative methods to tackle the complex difficulties of discovering drugs for AD.

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References

  1. EskandariS. SajadimajdS. AlaeiL. SoheilikhahZ. DerakhshankhahH. BahramiG. Targeting common signaling pathways for the treatment of stroke and Alzheimer’s: A comprehensive review.Neurotox. Res.20213951589161210.1007/s12640‑021‑00381‑734169405
     [Google Scholar]
  2. MathewA. BalajiEV. PaiSRK. KishoreA. PaiV. PemmireddyR. Current drug targets in Alzheimer's associated memory impairment: A comprehensive review.CNS Neurol Disord Drug Targets.202322225527510.2174/1871527321666220401124719.
     [Google Scholar]
  3. AnandA. PatienceA.A. SharmaN. KhuranaN. The present and future of pharmacotherapy of Alzheimer’s disease: A comprehensive review.Eur. J. Pharmacol.201781536437510.1016/j.ejphar.2017.09.04328978455
     [Google Scholar]
  4. AlhazmiH.A. AlbrattyM. An update on the novel and approved drugs for Alzheimer disease.Saudi Pharm. J.202230121755176410.1016/j.jsps.2022.10.00436601504
     [Google Scholar]
  5. ManzoorS. HodaN. A comprehensive review of monoamine oxidase inhibitors as Anti-Alzheimer’s disease agents: A review.Eur. J. Med. Chem.202020611278710.1016/j.ejmech.2020.11278732942081
     [Google Scholar]
  6. VogrincD. GoričarK. DolžanV. Genetic variability in molecular pathways implicated in Alzheimer’s disease: A comprehensive review.Front. Aging Neurosci.20211364690110.3389/fnagi.2021.64690133815092
     [Google Scholar]
  7. ReitzC. MayeuxR. Alzheimer disease: Epidemiology, diagnostic criteria, risk factors and biomarkers.Biochem. Pharmacol.201488464065110.1016/j.bcp.2013.12.02424398425
     [Google Scholar]
  8. MayeuxR. SternY. Epidemiology of Alzheimer disease.Cold Spring Harb. Perspect. Med.201228a00623910.1101/cshperspect.a00623922908189
     [Google Scholar]
  9. ApostolovaL.G. Alzheimer disease.Continuum (Minneap. Minn.)2016222, Dementia41943410.1212/CON.000000000000030727042902
     [Google Scholar]
  10. SabbaghM.N. CooperK. DeLangeJ. StoehrJ.D. ThindK. LahtiT. ReisbergB. SueL. VeddersL. FlemingS.R. BeachT.G. Functional, global and cognitive decline correlates to accumulation of Alzheimer’s pathology in MCI and AD.Curr. Alzheimer Res.20107428028610.2174/15672051079116234019715548
     [Google Scholar]
  11. Bastos LeiteA.J. ScheltensP. BarkhofF. Pathological aging of the brain: An overview.Top. Magn. Reson. Imaging200415636938910.1097/01.rmr.0000168070.90113.dc16041289
     [Google Scholar]
  12. DuggerB.N. DavisK. Malek-AhmadiM. HentzJ.G. SandhuS. BeachT.G. AdlerC.H. CaselliR.J. JohnsonT.A. SerranoG.E. ShillH.A. BeldenC. Driver-DunckleyE. CavinessJ.N. SueL.I. JacobsonS. PowellJ. SabbaghM.N. Neuropathological comparisons of amnestic and nonamnestic mild cognitive impairment.BMC Neurol.201515114610.1186/s12883‑015‑0403‑426289075
     [Google Scholar]
  13. BraakH. BraakE. Evolution of the neuropathology of Alzheimer’s disease.Acta Neurol. Scand.199694S16531210.1111/j.1600‑0404.1996.tb05866.x8740983
     [Google Scholar]
  14. JackC.R.Jr Alzheimer disease: New concepts on its neurobiology and the clinical role imaging will play.Radiology2012263234436110.1148/radiol.1211043322517954
     [Google Scholar]
  15. SengokuR. Aging and Alzheimer’s disease pathology.Neuropathology2020401222910.1111/neup.1262631863504
     [Google Scholar]
  16. SamantaS. RameshM. GovindarajuT. Alzheimer's is a multifactorial disease. Alzheimers Dis202113410.1039/9781839162732‑00001.
     [Google Scholar]
  17. TatulianS.A. Challenges and hopes for Alzheimer’s disease.Drug Discov. Today20222741027104310.1016/j.drudis.2022.01.01635121174
     [Google Scholar]
  18. MohamedT. ShakeriA. RaoP.P.N. Amyloid cascade in Alzheimer’s disease: Recent advances in medicinal chemistry.Eur. J. Med. Chem.201611325827210.1016/j.ejmech.2016.02.04926945113
     [Google Scholar]
  19. ZhangC. Natural compounds that modulate BACE1-processing of amyloid-beta precursor protein in Alzheimer’s disease.Discov. Med.2012147618919723021373
     [Google Scholar]
  20. LiuZ. ZhangA. SunH. HanY. KongL. WangX. Two decades of new drug discovery and development for Alzheimer’s disease.RSC Advances20177106046605810.1039/C6RA26737H
     [Google Scholar]
  21. KontaxiC. PiccardoP. GillA.C. Lysine-directed post-translational modifications of tau protein in Alzheimer’s disease and related tauopathies.Front. Mol. Biosci.201745610.3389/fmolb.2017.0005628848737
     [Google Scholar]
  22. PrakashA. DhaliwalG.K. KumarP. MajeedA.B.A. Brain biometals and Alzheimer’s disease – boon or bane?Int. J. Neurosci.201712729910810.3109/00207454.2016.117411827044501
     [Google Scholar]
  23. WeekleyC.M. HeC. Developing drugs targeting transition metal homeostasis.Curr. Opin. Chem. Biol.201737263210.1016/j.cbpa.2016.12.01128040658
     [Google Scholar]
  24. HartmannJ. KiewertC. DuysenE.G. LockridgeO. GreigN.H. KleinJ. Excessive hippocampal acetylcholine levels in acetylcholinesterase-deficient mice are moderated by butyrylcholinesterase activity.J. Neurochem.200710051421142910.1111/j.1471‑4159.2006.04347.x17212694
     [Google Scholar]
  25. ChaseT.N. FarlowM.R. Clarence-SmithK. Donepezil plus solifenacin (CPC-201) treatment for Alzheimer’s disease.Neurotherapeutics201714240541610.1007/s13311‑016‑0511‑x28138837
     [Google Scholar]
  26. CraigL.A. HongN.S. McDonaldR.J. Revisiting the cholinergic hypothesis in the development of Alzheimer’s disease.Neurosci. Biobehav. Rev.20113561397140910.1016/j.neubiorev.2011.03.00121392524
     [Google Scholar]
  27. JiangL. LiuC. LeiblyD. LandauM. ZhaoM. HughesM.P. EisenbergD.S. Structure-based discovery of fiber-binding compounds that reduce the cytotoxicity of amyloid beta.eLife20132e0085710.7554/eLife.0085723878726
     [Google Scholar]
  28. KumarV. SahaA. RoyK. In silico modeling for dual inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes in Alzheimer’s disease.Comput. Biol. Chem.20208810735510.1016/j.compbiolchem.2020.10735532801088
     [Google Scholar]
  29. ListonD.R. NielsenJ.A. VillalobosA. ChapinD. JonesS.B. HubbardS.T. ShalabyI.A. RamirezA. NasonD. WhiteW.F. Pharmacology of selective acetylcholinesterase inhibitors: Implications for use in Alzheimer’s disease.Eur. J. Pharmacol.2004486191710.1016/j.ejphar.2003.11.08014751402
     [Google Scholar]
  30. NordbergA. SvenssonA.L. Cholinesterase inhibitors in the treatment of Alzheimer’s disease: A comparison of tolerability and pharmacology.Drug Saf.199819646548010.2165/00002018‑199819060‑000049880090
     [Google Scholar]
  31. SnyderS.W. LadrorU.S. WadeW.S. WangG.T. BarrettL.W. MatayoshiE.D. HuffakerH.J. KrafftG.A. HolzmanT.F. Amyloid-beta aggregation: Selective inhibition of aggregation in mixtures of amyloid with different chain lengths.Biophys. J.19946731216122810.1016/S0006‑3495(94)80591‑07811936
     [Google Scholar]
  32. AwasthiM. UpadhyayA.K. SinghS. PandeyV.P. DwivediU.N. Terpenoids as promising therapeutic molecules against Alzheimer’s disease: Amyloid beta- and acetylcholinesterase-directed pharmacokinetic and molecular docking analyses.Mol. Simul.201844111110.1080/08927022.2017.1334880
     [Google Scholar]
  33. VassarR.J. EC-01-03: Bace1, the beta-secretase enzyme: A leading therapeutic target for Alzheimer’s disease.Alzheimers Dement.2016127S_Part_3162P16210.1016/j.jalz.2016.06.289
     [Google Scholar]
  34. GourasG.K. OlssonT.T. HanssonO. β-Amyloid peptides and amyloid plaques in Alzheimer’s disease.Neurotherapeutics201512131110.1007/s13311‑014‑0313‑y25371168
     [Google Scholar]
  35. VassarR. KovacsD.M. YanR. WongP.C. The β-secretase enzyme BACE in health and Alzheimer’s disease: Regulation, cell biology, function, and therapeutic potential.J. Neurosci.20092941127871279410.1523/JNEUROSCI.3657‑09.200919828790
     [Google Scholar]
  36. AaldijkE. VermeirenY. The role of serotonin within the microbiota-gut-brain axis in the development of Alzheimer’s disease: A narrative review.Ageing Res. Rev.20227510155610.1016/j.arr.2021.10155634990844
     [Google Scholar]
  37. NykampM.J. ZorumskiC.F. ReiersenA.M. NicolG.E. CirritoJ. LenzeE.J. Opportunities for drug repurposing of serotonin reuptake inhibitors: Potential uses in inflammation, infection, cancer, neuroprotection, and Alzheimer’s disease prevention.Pharmacopsychiatry2022551242910.1055/a‑1686‑962034875696
     [Google Scholar]
  38. HeG. LuoW. LiP. RemmersC. NetzerW.J. HendrickJ. BettayebK. FlajoletM. GorelickF. WennogleL.P. GreengardP. Gamma-secretase activating protein is a therapeutic target for Alzheimer’s disease.Nature20104677311959810.1038/nature0932520811458
     [Google Scholar]
  39. TateB. McKeeT.D. LoureiroR.M.B. DuminJ.A. XiaW. PojasekK. AustinW.F. FullerN.O. HubbsJ.L. ShenR. JonkerJ. IvesJ. BronkB.S. Modulation of gamma-secretase for the treatment of Alzheimer’s disease.Int. J. Alzheimers Dis.2012201211010.1155/2012/21075623320246
     [Google Scholar]
  40. MorawskiM. SchillingS. KreuzbergerM. WaniekA. JägerC. KochB. CynisH. KehlenA. ArendtT. Hartlage-RübsamenM. DemuthH.U. RoßnerS. Glutaminyl cyclase in human cortex: Correlation with (pGlu)-amyloid-β load and cognitive decline in Alzheimer’s disease.J. Alzheimers Dis.201439238540010.3233/JAD‑13153524164736
     [Google Scholar]
  41. Hielscher-MichaelS. GriehlC. BuchholzM. DemuthH.U. ArnoldN. WessjohannL. Natural products from microalgae with potential against Alzheimer’s disease: Sulfolipids are potent glutaminyl cyclase inhibitors.Mar. Drugs2016141120310.3390/md1411020327827845
     [Google Scholar]
  42. García-OstaA. Cuadrado-TejedorM. García-BarrosoC. OyarzábalJ. FrancoR. Phosphodiesterases as therapeutic targets for Alzheimer’s disease.ACS Chem. Neurosci.201231183284410.1021/cn300090723173065
     [Google Scholar]
  43. ShengJ. ZhangS. WuL. KumarG. LiaoY. GkP. FanH. Inhibition of phosphodiesterase: A novel therapeutic target for the treatment of mild cognitive impairment and Alzheimer’s disease.Front. Aging Neurosci.202214101918710.3389/fnagi.2022.101918736268188
     [Google Scholar]
  44. WuY. LiZ. HuangY.Y. WuD. LuoH.B. Novel phosphodiesterase inhibitors for cognitive improvement in Alzheimer’s disease: Miniperspective.J. Med. Chem.201861135467548310.1021/acs.jmedchem.7b0137029363967
     [Google Scholar]
  45. PrickaertsJ. HeckmanP.R.A. BloklandA. Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease.Expert Opin. Investig. Drugs20172691033104810.1080/13543784.2017.136436028772081
     [Google Scholar]
  46. CruzJ.C. TsaiL.H. CDK5 deregulation in the pathogenesis of Alzheimer’s disease.Trends Mol. Med.200410945245810.1016/j.molmed.2004.07.00115350898
     [Google Scholar]
  47. BhounsuleA.S. BhattL.K. PrabhavalkarK.S. OzaM. Cyclin dependent kinase 5: A novel avenue for Alzheimer’s disease.Brain Res. Bull.2017132283810.1016/j.brainresbull.2017.05.00628526617
     [Google Scholar]
  48. BalaramanY. LimayeA.R. LeveyA.I. SrinivasanS. Glycogen synthase kinase 3β and Alzheimer’s disease: Pathophysiological and therapeutic significance.Cell. Mol. Life Sci.200663111226123510.1007/s00018‑005‑5597‑y16568235
     [Google Scholar]
  49. BoutajangoutA. LeroyK. AutheletM AndertonB. BrionJ-P. WoodgettJ. The active form of glycogen synthase kinase-3? is associated with granulovacuolar degeneration in neurons in Alzheimer’s disease.Acta Neuropathol.20021032919910.1007/s00401010043511810173
     [Google Scholar]
  50. BenziG. MorettiA. Are reactive oxygen species involved in Alzheimer’s disease?Neurobiol. Aging199516466167410.1016/0197‑4580(95)00066‑N8544918
     [Google Scholar]
  51. KumarM.J. AndersenJ.K. Perspectives on MAO-B in aging and neurological disease: Where do we go from here?Mol. Neurobiol.2004301779010.1385/MN:30:1:07715247489
     [Google Scholar]
  52. AhmedH.A. IshratT. The brain AT2R-a potential target for therapy in Alzheimer’s disease and vascular cognitive impairment: A comprehensive review of clinical and experimental therapeutics.Mol. Neurobiol.20205783458348410.1007/s12035‑020‑01964‑932533467
     [Google Scholar]
  53. FleetJ.L. McArthurE. PatelA. WeirM.A. Montero-OdassoM. GargA.X. Risk of rhabdomyolysis with donepezil compared with rivastigmine or galantamine: A population-based cohort study.CMAJ201919137E1018E102410.1503/cmaj.19033731527187
     [Google Scholar]
  54. TariotP. SallowayS. YardleyJ. MackellJ. MolineM. Long-term safety and tolerability of donepezil 23 mg in patients with moderate to severe Alzheimer’s disease.BMC Res. Notes20125128310.1186/1756‑0500‑5‑28322681723
     [Google Scholar]
  55. FolchJ. EttchetoM. PetrovD. AbadS. PedrósI. MarinM. OlloquequiJ. CaminsA. Review of the advances in treatment for Alzheimer disease: Strategies for combating β-amyloid protein.Neurología (English Edition)2018331475810.1016/j.nrleng.2015.03.01925976937
     [Google Scholar]
  56. PanzaF. LozuponeM. LogroscinoG. ImbimboB.P. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease.Nat. Rev. Neurol.2019152738810.1038/s41582‑018‑0116‑630610216
     [Google Scholar]
  57. MelchiorriD. MerloS. MicallefB. BorgJ.J. DráfiF. Alzheimer’s disease and neuroinflammation: Will new drugs in clinical trials pave the way to a multi-target therapy?Front. Pharmacol.202314119641310.3389/fphar.2023.119641337332353
     [Google Scholar]
  58. TobehN.S. BruceK.D. Emerging Alzheimer’s disease therapeutics: Promising insights from lipid metabolism and microglia-focused interventions.Front. Aging Neurosci.202315125901210.3389/fnagi.2023.125901238020773
     [Google Scholar]
  59. GklinosP. PapadopoulouM. StanulovicV. MitsikostasD.D. PapadopoulosD. Monoclonal antibodies as neurological therapeutics.Pharmaceuticals (Basel)20211429210.3390/ph1402009233530460
     [Google Scholar]
  60. NimmoJ.T. KellyL. VermaA. CarareR.O. NicollJ.A.R. DodartJ.C. Amyloid-β and α-synuclein immunotherapy: From experimental studies to clinical trials.Front. Neurosci.20211573385710.3389/fnins.2021.73385734539340
     [Google Scholar]
  61. SarazinM. de SouzaL.C. LehéricyS. DuboisB. Clinical and research diagnostic criteria for Alzheimer’s disease.Neuroimaging Clin. N. Am.2012221233210.1016/j.nic.2011.11.00422284731
     [Google Scholar]
  62. LövheimH. GilthorpeJ. AdolfssonR. NilssonL.G. ElghF. Reactivated herpes simplex infection increases the risk of Alzheimer’s disease.Alzheimers Dement.201511659359910.1016/j.jalz.2014.04.52225043910
     [Google Scholar]
  63. AmesD. BurnsA. O’BrienJ.T. Dementia.LondonCRC Press201010.1201/b13196
     [Google Scholar]
  64. GiacobiniE. GoldG. Alzheimer disease therapy-moving from amyloid-β to tau.Nat. Rev. Neurol.201391267768610.1038/nrneurol.2013.22324217510
     [Google Scholar]
  65. McKeithI. O’BrienJ. WalkerZ. TatschK. BooijJ. DarcourtJ. PadovaniA. GiubbiniR. BonuccelliU. VolterraniD. HolmesC. KempP. TabetN. MeyerI. ReiningerC. Sensitivity and specificity of dopamine transporter imaging with 123I-FP-CIT SPECT in dementia with Lewy bodies: A phase III, multicentre study.Lancet Neurol.20076430531310.1016/S1474‑4422(07)70057‑117362834
     [Google Scholar]
  66. SharmaS. LipincottW. Biomarkers in Alzheimer’s disease-recent update.Curr. Alzheimer Res.2017149991110.2174/1567205014666170220141822
     [Google Scholar]
  67. BlennowK. Biomarkers in Alzheimer’s disease drug development.Nat. Med.201016111218122210.1038/nm.222121052077
     [Google Scholar]
  68. DodelR. HampelH. DepboyluC. LinS. GaoF. SchockS. JäckelS. WeiX. BuergerK. HöftC. HemmerB. MöllerH.J. FarlowM. OertelW.H. SommerN. DuY. Human antibodies against amyloid β peptide: A potential treatment for Alzheimer’s disease.Ann. Neurol.200252225325610.1002/ana.1025312210803
     [Google Scholar]
  69. HayneD.J. LimS. DonnellyP.S. Metal complexes designed to bind to amyloid-β for the diagnosis and treatment of Alzheimer’s disease.Chem. Soc. Rev.201443196701671510.1039/C4CS00026A24671229
     [Google Scholar]
  70. ForlenzaO.V. De-PaulaV.J.R. DinizB.S.O. Neuroprotective effects of lithium: Implications for the treatment of Alzheimer’s disease and related neurodegenerative disorders.ACS Chem. Neurosci.20145644345010.1021/cn500030924766396
     [Google Scholar]
  71. HeinrichM. Lee TeohH. Galanthamine from snowdrop-the development of a modern drug against Alzheimer’s disease from local Caucasian knowledge.J. Ethnopharmacol.2004922-314716210.1016/j.jep.2004.02.01215137996
     [Google Scholar]
  72. BartusR.T. DeanR.L.III BeerB. LippaA.S. The cholinergic hypothesis of geriatric memory dysfunction.Science1982217455840841410.1126/science.70460517046051
     [Google Scholar]
  73. SchliebsR. ArendtT. The significance of the cholinergic system in the brain during aging and in Alzheimer’s disease.J. Neural Transm. (Vienna)2006113111625164410.1007/s00702‑006‑0579‑217039298
     [Google Scholar]
  74. RelmanA.S. Tacrine as a treatment for Alzheimer’s dementia: Editor’s note. An interim report from the FDA. A response from Summers et al.N. Engl. J. Med.1991324534935210.1056/NEJM1991013132405251986300
     [Google Scholar]
  75. BirksJ.S. HarveyR.J. Donepezil for dementia due to Alzheimer’s disease.Cochrane Libr.201820186CD00119010.1002/14651858.CD001190.pub329923184
     [Google Scholar]
  76. LoyC. SchneiderL. Galantamine for Alzheimer’s disease and mild cognitive impairment.Cochrane Libr.200620091CD00174710.1002/14651858.CD001747.pub316437436
     [Google Scholar]
  77. McArthurR.A. GrayJ. SchreiberR. Cognitive effects of muscarinic M1 functional agonists in non-human primates and clinical trials.Curr. Opin. Investig. Drugs201011774076020571970
     [Google Scholar]
  78. FuL.M. LiJ.T. A systematic review of single chinese herbs for Alzheimer’s disease treatment.Evid. Based Complement. Alternat. Med.20112011164028410.1093/ecam/nep13619737808
     [Google Scholar]
  79. RafiiM.S. WalshS. LittleJ.T. BehanK. ReynoldsB. WardC. JinS. ThomasR. AisenP.S. A phase II trial of huperzine A in mild to moderate Alzheimer disease.Neurology201176161389139410.1212/WNL.0b013e318216eb7b21502597
     [Google Scholar]
  80. JiaJ. ZhaoQ. LiuY. GuiY. LiuG. ZhuD. YuC. HongZ. Phase I study on the pharmacokinetics and tolerance of ZT-1, a prodrug of huperzine A, for the treatment of Alzheimer’s disease.Acta Pharmacol. Sin.201334797698210.1038/aps.2013.723624756
     [Google Scholar]
  81. CoelhoF. BirksJ. Physostigmine for Alzheimer’s disease.Cochrane Database Syst. Rev.200120012CD00149911405996
     [Google Scholar]
  82. WinbladB. GiacobiniE. FrölichL. FriedhoffL.T. BruinsmaG. BeckerR.E. GreigN.H. Phenserine efficacy in Alzheimer’s disease.J. Alzheimers Dis.20112241201120810.3233/JAD‑2010‑10131120930279
     [Google Scholar]
  83. WeinrebO. AmitT. Bar-AmO. YoudimM.B. Ladostigil: A novel multimodal neuroprotective drug with cholinesterase and brain-selective monoamine oxidase inhibitory activities for Alzheimer’s disease treatment.Curr. Drug Targets201213448349410.2174/13894501279949979422280345
     [Google Scholar]
  84. FisherA. Cholinergic modulation of amyloid precursor protein processing with emphasis on M1 muscarinic receptor: Perspectives and challenges in treatment of Alzheimer’s disease.J. Neurochem.2012120s1223310.1111/j.1471‑4159.2011.07507.x22122190
     [Google Scholar]
  85. Grundke-IqbalI. IqbalK. TungY.C. QuinlanM. WisniewskiH.M. BinderL.I. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology.Proc. Natl. Acad. Sci. USA198683134913491710.1073/pnas.83.13.49133088567
     [Google Scholar]
  86. LindwallG. ColeR.D. Phosphorylation affects the ability of tau protein to promote microtubule assembly.J. Biol. Chem.198425985301530510.1016/S0021‑9258(17)42989‑96425287
     [Google Scholar]
  87. ShuklaV. SkuntzS. PantH.C. Deregulated CDK5 activity is involved in inducing Alzheimer’s disease.Arch. Med. Res.201243865566210.1016/j.arcmed.2012.10.01523142263
     [Google Scholar]
  88. YarzaR. VelaS. SolasM. RamirezM.J. c-Jun N-terminal kinase (JNK) signaling as a therapeutic target for Alzheimer’s disease.Front. Pharmacol.2016632110.3389/fphar.2015.0032126793112
     [Google Scholar]
  89. SontagJ.M. SontagE. Protein phosphatase 2A dysfunction in Alzheimer's disease.Front. Mol. Neurosci.201471610.3389/fnmol.2014.0001624653673
     [Google Scholar]
  90. CongdonE.E. SigurdssonE.M. Tau-targeting therapies for Alzheimer disease.Nat. Rev. Neurol.201814739941510.1038/s41582‑018‑0013‑z29895964
     [Google Scholar]
  91. JadhavS. KatinaS. KovacA. KazmerovaZ. NovakM. ZilkaN. Truncated tau deregulates synaptic markers in rat model for human tauopathy.Front. Cell. Neurosci.201592410.3389/fncel.2015.0002425755633
     [Google Scholar]
  92. RapoportM. DawsonH.N. BinderL.I. VitekM.P. FerreiraA. Tau is essential to β-amyloid-induced neurotoxicity.Proc. Natl. Acad. Sci. USA20029996364636910.1073/pnas.09213619911959919
     [Google Scholar]
  93. Meraz-RíosM.A. Lira-De LeónK.I. Campos-PeñaV. De Anda-HernándezM.A. Mena-LópezR. Tau oligomers and aggregation in Alzheimer’s disease.J. Neurochem.201011261353136710.1111/j.1471‑4159.2009.06511.x19943854
     [Google Scholar]
  94. IttnerA. BertzJ. SuhL.S. StevensC.H. GötzJ. IttnerL.M. Tau-targeting passive immunization modulates aspects of pathology in tau transgenic mice.J. Neurochem.2015132113514510.1111/jnc.1282125041093
     [Google Scholar]
  95. SigurdssonE.M. Tau immunotherapies for Alzheimer’s disease and related tauopathies: Progress and potential pitfalls.J. Alzheimers Dis.201864s1S555S56510.3233/JAD‑17993729865056
     [Google Scholar]
  96. ZuckermanJ.E. DavisM.E. Clinical experiences with systemically administered siRNA-based therapeutics in cancer.Nat. Rev. Drug Discov.2015141284385610.1038/nrd468526567702
     [Google Scholar]
  97. FinkelR.S. ChiribogaC.A. VajsarJ. DayJ.W. MontesJ. De VivoD.C. YamashitaM. RigoF. HungG. SchneiderE. NorrisD.A. XiaS. BennettC.F. BishopK.M. Treatment of infantile-onset spinal muscular atrophy with nusinersen: A phase 2, open-label, dose-escalation study.Lancet2016388100633017302610.1016/S0140‑6736(16)31408‑827939059
     [Google Scholar]
  98. AsgharU. WitkiewiczA.K. TurnerN.C. KnudsenE.S. The history and future of targeting cyclin-dependent kinases in cancer therapy.Nat. Rev. Drug Discov.201514213014610.1038/nrd450425633797
     [Google Scholar]
  99. KhalilH.S. MitevV. VlaykovaT. CavicchiL. ZhelevN. Discovery and development of Seliciclib. How systems biology approaches can lead to better drug performance.J. Biotechnol.2015202404910.1016/j.jbiotec.2015.02.03225747275
     [Google Scholar]
  100. MayP.C. DeanR.A. LoweS.L. MartenyiF. SheehanS.M. BoggsL.N. MonkS.A. MathesB.M. MergottD.J. WatsonB.M. StoutS.L. TimmD.E. Smith LaBellE. GonzalesC.R. NakanoM. JheeS.S. YenM. EreshefskyL. LindstromT.D. CalligaroD.O. CockeP.J. Greg HallD. FriedrichS. CitronM. AudiaJ.E. Robust central reduction of amyloid-β in humans with an orally available, non-peptidic β-secretase inhibitor.J. Neurosci.20113146165071651610.1523/JNEUROSCI.3647‑11.201122090477
     [Google Scholar]
  101. WillisB. MartenyiF. DeanR. LoweS. NakanoM. MonkS. GonzalesC. MergottD. DaughertyL. CitronM. MayP. P3-359: Central BACE1 inhibition by LY2886721 produces opposing effects on APP processing as reflected by cerebrospinal fluid sAPPalpha and sAPPbeta.Alzheimers Dement.201284S_Part_16582P58210.1016/j.jalz.2012.05.1584
     [Google Scholar]
  102. LaiR. AlbalaB. KaplowJ.M. AluriJ. YenM. SatlinA. O1-06-05: First-in-human study of E2609, a novel BACE1 inhibitor, demonstrates prolonged reductions in plasma beta-amyloid levels after single dosing.Alzheimers Dement.201284S_Part_396P9610.1016/j.jalz.2012.05.237
     [Google Scholar]
  103. HenleyD.B. MayP.C. DeanR.A. SiemersE.R. Development of semagacestat (LY450139), a functional γ-secretase inhibitor, for the treatment of Alzheimer’s disease.Expert Opin. Pharmacother.200910101657166410.1517/1465656090304498219527190
     [Google Scholar]
  104. MartoneR.L. ZhouH. AtchisonK. ComeryT. XuJ.Z. HuangX. GongX. JinM. KreftA. HarrisonB. MayerS.C. AschmiesS. GonzalesC. ZaleskaM.M. RiddellD.R. WagnerE. LuP. SunS.C. Sonnenberg-ReinesJ. OganesianA. AdkinsK. LeachM.W. ClarkeD.W. HurynD. Abou-GharbiaM. MagoldaR. BardJ. FrickG. RajeS. ForlowS.B. BallietC. BurczynskiM.E. ReinhartP.H. WanH.I. PangalosM.N. JacobsenJ.S. Begacestat (GSI-953): A novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein γ-secretase for the treatment of Alzheimer’s disease.J. Pharmacol. Exp. Ther.2009331259860810.1124/jpet.109.15297519671883
     [Google Scholar]
  105. HashimotoT. IshibashiA. HagiwaraH. MurataY. TakenakaO. MiyagawaT. P1-236: E2012: A novel gamma-secretase modulator-pharmacology part.Alzheimers Dement.201064S_Part_8S242S24210.1016/j.jalz.2010.05.787
     [Google Scholar]
  106. WinbladB. AndreasenN. MinthonL. FloesserA. ImbertG. DumortierT. MaguireR.P. BlennowK. LundmarkJ. StaufenbielM. OrgogozoJ.M. GrafA. Safety, tolerability, and antibody response of active Aβ immunotherapy with CAD106 in patients with Alzheimer’s disease: Randomised, double-blind, placebo-controlled, first-in-human study.Lancet Neurol.201211759760410.1016/S1474‑4422(12)70140‑022677258
     [Google Scholar]
  107. GalimbertiD. GhezziL. ScarpiniE. Immunotherapy against amyloid pathology in Alzheimer’s disease.J. Neurol. Sci.20133331-2505410.1016/j.jns.2012.12.01323299047
     [Google Scholar]
  108. SavageM.J. WuG. McCampbellA. WessnerK.R. CitronM. LiangX. HsiehS. WolfeA.L. KinneyG.G. RosenL.B. RengerJ.J. O3-07-03: A novel multivalent Abeta peptide vaccine with preclinical evidence of a central immune response that generates antisera recognizing a wide range of Abeta peptide species.Alzheimers Dement.201064S_Part_5S142S14210.1016/j.jalz.2010.05.437
     [Google Scholar]
  109. Lambracht-WashingtonD. QuB.X. FuM. AndersonL.D.Jr StüveO. EagarT.N. RosenbergR.N. DNA immunization against amyloid beta 42 has high potential as safe therapy for Alzheimer’s disease as it diminishes antigen-specific Th1 and Th17 cell proliferation.Cell. Mol. Neurobiol.201131686787410.1007/s10571‑011‑9680‑721625960
     [Google Scholar]
  110. SamadiH. SultzerD. Solanezumab for Alzheimer’s disease.Expert Opin. Biol. Ther.201111678779810.1517/14712598.2011.57857321504387
     [Google Scholar]
  111. FreemanG.B. LinJ.C. PonsJ. RahaN.M. 39-week toxicity and toxicokinetic study of ponezumab (PF-04360365) in cynomolgus monkeys with 12-week recovery period.J. Alzheimers Dis.201228353154110.3233/JAD‑2011‑11086922045481
     [Google Scholar]
  112. LeyheT. AndreasenN. SimeoniM. ReichA. von ArnimC.A.F. TongX. YeoA. KhanS. LoercherA. ChalkerM. HottensteinC. ZetterbergH. HilpertJ. MistryP. Modulation of β-amyloid by a single dose of GSK933776 in patients with mild Alzheimer’s disease: A phase I study.Alzheimers Res. Ther.2014621910.1186/alzrt24924716469
     [Google Scholar]
  113. GervaisF. PaquetteJ. MorissetteC. KrzywkowskiP. YuM. AzziM. LacombeD. KongX. AmanA. LaurinJ. SzarekW.A. TremblayP. Targeting soluble Aβ peptide with Tramiprosate for the treatment of brain amyloidosis.Neurobiol. Aging200728453754710.1016/j.neurobiolaging.2006.02.01516675063
     [Google Scholar]
  114. HerrmannN. ChauS.A. KircanskiI. LanctôtK.L. Current and emerging drug treatment options for Alzheimer’s disease: A systematic review.Drugs201171152031206510.2165/11595870‑000000000‑0000021985169
     [Google Scholar]
  115. MaK. ThomasonL.A.M. McLaurinJ. scyllo-Inositol, preclinical, and clinical data for Alzheimer’s disease.Adv. Pharmacol.20126417721210.1016/B978‑0‑12‑394816‑8.00006‑422840748
     [Google Scholar]
  116. SampsonE.L. JenagaratnamL. McShaneR. Metal protein attenuating compounds for the treatment of Alzheimer’s dementia.Cochrane Libr.201420142CD00538010.1002/14651858.CD005380.pub524563468
     [Google Scholar]
  117. BursteinA.H. GrimesI. GalaskoD.R. AisenP.S. SabbaghM. MjalliA.M.M. Effect of TTP488 in patients with mild to moderate Alzheimer’s disease.BMC Neurol.20141411210.1186/1471‑2377‑14‑1224423155
     [Google Scholar]
  118. NagaharaA.H. MerrillD.A. CoppolaG. TsukadaS. SchroederB.E. ShakedG.M. WangL. BleschA. KimA. ConnerJ.M. RockensteinE. ChaoM.V. KooE.H. GeschwindD. MasliahE. ChibaA.A. TuszynskiM.H. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease.Nat. Med.200915333133710.1038/nm.191219198615
     [Google Scholar]
  119. HeftiF. Nerve growth factor promotes survival of septal cholinergic neurons after fimbrial transections.J. Neurosci.1986682155216210.1523/JNEUROSCI.06‑08‑02155.19863746405
     [Google Scholar]
  120. FukushimaT. NakamuraA. IwakamiN. NakadaY. HattoriH. HokiS. YamaguchiH. NakagawaM. TerashimaN. NaritaH. T-817MA, a neuroprotective agent, attenuates the motor and cognitive impairments associated with neuronal degeneration in P301L tau transgenic mice.Biochem. Biophys. Res. Commun.2011407473073410.1016/j.bbrc.2011.03.09121439944
     [Google Scholar]
  121. EckertS.H. EckmannJ. RennerK. EckertG.P. LeunerK. MullerW.E. Dimebon ameliorates amyloid-β induced impairments of mitochondrial form and function.J. Alzheimers Dis.2012311213210.3233/JAD‑2012‑12031022475801
     [Google Scholar]
  122. QuintanillaR.A. Matthews-RobersonT.A. DolanP.J. JohnsonG.V.W. Caspase-cleaved tau expression induces mitochondrial dysfunction in immortalized cortical neurons: Implications for the pathogenesis of Alzheimer disease.J. Biol. Chem.200928428187541876610.1074/jbc.M80890820019389700
     [Google Scholar]
  123. GovindarajuluM. PinkyP.D. BloemerJ. GhaneiN. SuppiramaniamV. AminR. Signaling mechanisms of selective PPARγ modulators in Alzheimer’s disease.PPAR Res.2018201812010.1155/2018/201067530420872
     [Google Scholar]
  124. LandrethG. JiangQ. MandrekarS. HenekaM. PPARgamma agonists as therapeutics for the treatment of Alzheimer’s disease.Neurotherapeutics20085348148910.1016/j.nurt.2008.05.00318625459
     [Google Scholar]
  125. LandrethG. Therapeutic use of agonists of the nuclear receptor PPARgamma in Alzheimer’s disease.Curr. Alzheimer Res.20074215916410.2174/15672050778036209217430241
     [Google Scholar]
  126. ZhuM. De SimoneA. SchenkD. TothG. DobsonC.M. VendruscoloM. Identification of small-molecule binding pockets in the soluble monomeric form of the Aβ42 peptide.J. Chem. Phys.2013139303510110.1063/1.4811831
     [Google Scholar]
  127. Scherzer-AttaliR. PellarinR. ConvertinoM. Frydman-MaromA. Egoz-MatiaN. PeledS. Levy-SakinM. ShalevD.E. CaflischA. GazitE. SegalD. Complete phenotypic recovery of an Alzheimer’s disease model by a quinone-tryptophan hybrid aggregation inhibitor.PLoS One201056e1110110.1371/journal.pone.001110120559435
     [Google Scholar]
  128. ZhangT. XuW. MuY. DerreumauxP. Atomic and dynamic insights into the beneficial effect of the 1,4-naphthoquinon-2-yl-L-tryptophan inhibitor on Alzheimer’s Aβ1-42 dimer in terms of aggregation and toxicity.ACS Chem. Neurosci.20145214815910.1021/cn400197x24246047
     [Google Scholar]
  129. BerthoumieuO. NguyenP.H. Castillo-FriasM.P. FerreS. TarusB. Nasica-LabouzeJ. NoëlS. SaurelO. RamponC. DoigA.J. DerreumauxP. FallerP. Combined experimental and simulation studies suggest a revised mode of action of the anti-Alzheimer disease drug NQ-Trp.Chemistry20152136126571266610.1002/chem.20150088826179053
     [Google Scholar]
  130. ZangY. NingJ. LiuK. ShangM. ZangC. LiC. MaJ. ChenX. MaJ. LiG. YangY. BaoX. ZhangD. ZhangD. Design, synthesis and biological evaluation of pyranocarbazole derivatives against Alzheimer’s disease, with antioxidant, neuroprotective and cognition enhancing properties.Bioorg. Chem.202212910617910.1016/j.bioorg.2022.10617936244322
     [Google Scholar]
  131. DongM. LiH. HuD. ZhaoW. ZhuX. AiH. Molecular dynamics study on the inhibition mechanisms of drugs CQ1–3 for Alzheimer amyloid-β40 aggregation induced by Cu2+.ACS Chem. Neurosci.20167559961410.1021/acschemneuro.5b0034326871000
     [Google Scholar]
  132. LeónR. GarciaA.G. Marco-ContellesJ. Recent advances in the multitarget-directed ligands approach for the treatment of Alzheimer’s disease.Med. Res. Rev.201333113918910.1002/med.2024821793014
     [Google Scholar]
  133. ChuH. ZhangA. HanY. LuS. KongL. HanJ. LiuZ. SunH. WangX. Metabolomics approach to explore the effects of Kai-Xin-San on Alzheimer’s disease using UPLC/ESI-Q-TOF mass spectrometry.J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.20161015-1016506110.1016/j.jchromb.2016.02.00726896572
     [Google Scholar]
  134. ZhangA.H. SunH. YanG.L. WangP. HanY. WangX.J. Chinmedomics: A new strategy for research of traditional Chinese medicine.Zhongguo Zhongyao Zazhi201540456957626137671
     [Google Scholar]
/content/journals/cpd/10.2174/0113816128334916241006195142
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Alzheimer's Disease Protein Targets: Comprehensive Review and Future Directions
Curr. Pharm. Des. 31, 1347 (2025); https://doi.org/10.2174/0113816128334916241006195142
/content/journals/cpd/10.2174/0113816128334916241006195142
/content/journals/cpd/10.2174/0113816128334916241006195142
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  • Article Type:     Review Article
Keyword(s): Alzheimer’s disease; amyloid plaque; cholinergic dysfunction; N-methyl d-aspartate; neurodegenerative; tau protein

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