Recent Advancements in Strategies for Abnormal Protein Clearance in
Alzheimer's Disease

Baofeng      Gong; Wenbo      Ji; Xiaohan      Chen; Peng      Li; Wenbin      Cheng; Yuchen      Zhao; Bin      He; Jianhua      Zhuang; Jie      Gao; You      Yin

doi:10.2174/1389557522666220214092824

Abstract

Alzheimer's disease (AD) is an intricate neurodegenerative disease with chronic and progressive development whose typical neuropathological features encompass senile plaques and neurofibrillary tangles, respectively formed by the extracellular deposition of amyloid-beta (Aβ) and the intracellular accumulation of hyperphosphorylated tau protein in the brain, particularly in limbic and cortical regions. The pathological changes are considered to be caused by the loss of Aβ and tau protein clearance mechanisms under pathological conditions, which leads to an imbalance between the rates of clearance and production. Consequently, the main strategies for treating AD aim to reduce the production of Aβ and hyperphosphorylated tau protein in the brain, inhibit their accumulation, or accelerate their clearance. Although drugs utilizing these therapeutic strategies have been studied successively, their therapeutic effects have generally been less than ideal. Fortunately, recent advances have been made in clearance strategies for these abnormally expressed proteins, including immunotherapies and nanomedicines targeting Aβ or tau, which could represent an important breakthrough for treating AD. Here, we review recent development of the strategies for the removal of abnormal proteins and provide new ideas and methods for treating AD.

Keywords: Alzheimer’s disease, amyloid, tau, abnormal protein, clearance strategies, immunotherapy, nanomedicine.

« Previous Next »

Graphical Abstract

[1] 
Huang, H.C.; Jiang, Z.F. Accumulated amyloid-beta peptide and hyperphosphorylated tau protein: Relationship and links in Alzheimer’s disease. J. Alzheimers Dis.,  2009, 16(1), 15-27.
[http://dx.doi.org/10.3233/JAD-2009-0960] [PMID: 19158417] 
[2] 
Alzheimer’s disease facts and figures. Alzheimers Dement.,  2020, 2020
[http://dx.doi.org/10.1002/alz.12068] 
[3] 
Briggs, R.; Kennelly, S.P.; O’Neill, D. Drug treatments in Alzheimer’s disease. Clin. Med. (Lond.),  2016, 16(3), 247-253.
[http://dx.doi.org/10.7861/clinmedicine.16-3-247] [PMID: 27251914] 
[4] 
Jack, C.R., Jr; Bennett, D.A.; Blennow, K.; Carrillo, M.C.; Dunn, B.; Haeberlein, S.B.; Holtzman, D.M.; Jagust, W.; Jessen, F.; Karlawish, J.; Liu, E.; Molinuevo, J.L.; Montine, T.; Phelps, C.; Rankin, K.P.; Rowe, C.C.; Scheltens, P.; Siemers, E.; Snyder, H.M.; Sperling, R. NIA-AA Research framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement.,  2018, 14(4), 535-562.
[http://dx.doi.org/10.1016/j.jalz.2018.02.018] [PMID: 29653606] 
[5] 
Han, P.; Shi, J. Theoretical analysis of the synergy of amyloid and tau in Alzheimer’s disease. J. Alzheimers Dis.,  2016, 52(4), 1461-1470.
[http://dx.doi.org/10.3233/JAD-151206] [PMID: 27104897] 
[6] 
Ricciarelli, R.; Fedele, E. The amyloid cascade hypothesis in Alzheimer’s disease: It’s time to change our mind. Curr. Neuropharmacol.,  2017, 15(6), 926-935.
[http://dx.doi.org/10.2174/1570159X15666170116143743] [PMID: 28093977] 
[7] 
Long, J.M.; Holtzman, D.M. Alzheimer disease: An update on pathobiology and treatment strategies. Cell,  2019, 179(2), 312-339.
[http://dx.doi.org/10.1016/j.cell.2019.09.001] [PMID: 31564456] 
[8] 
Hampel, H.; Mesulam, M.M.; Cuello, A.C.; Farlow, M.R.; Giacobini, E.; Grossberg, G.T.; Khachaturian, A.S.; Vergallo, A.; Cavedo, E.; Snyder, P.J.; Khachaturian, Z.S. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain,  2018, 141(7), 1917-1933.
[http://dx.doi.org/10.1093/brain/awy132] [PMID: 29850777] 
[9] 
Harilal, S.; Jose, J.; Parambi, D.G.T.; Kumar, R.; Mathew, G.E.; Uddin, M.S.; Kim, H.; Mathew, B. Advancements in nanotherapeutics for Alzheimer’s disease: Current perspectives. J. Pharm. Pharmacol.,  2019, 71(9), 1370-1383.
[http://dx.doi.org/10.1111/jphp.13132] [PMID: 31304982] 
[10] 
Swerdlow, R.H. Is aging part of Alzheimer’s disease, or is Alzheimer’s disease part of aging? Neurobiol. Aging,  2007, 28(10), 1465-1480.
[http://dx.doi.org/10.1016/j.neurobiolaging.2006.06.021] [PMID: 16876913] 
[11] 
Zhang, F.; Zhong, R.; Cheng, C.; Li, S.; Le, W. New therapeutics beyond amyloid-β and tau for the treatment of Alzheimer’s disease. Acta Pharmacol. Sin.,  2021, 42(9), 1382-1389.
[http://dx.doi.org/10.1038/s41401-020-00565-5] [PMID: 33268824] 
[12] 
Du, H.; ShiDu, Yan S. Unlocking the door to neuronal woes in Alzheimer’s disease: Aβ and mitochondrial permeability transition pore. Pharmaceuticals (Basel),  2010, 3(6), 1936-1948.
[http://dx.doi.org/10.3390/ph3061936] [PMID: 27713335] 
[13] 
Shevtsova, E.F.; Maltsev, A.V.; Vinogradova, D.V.; Shevtsov, P.N.; Bachurin, S.O. Mitochondria as a promising target for developing novel agents for treating Alzheimer’s disease. Med. Res. Rev.,  2021, 41(2), 803-827.
[http://dx.doi.org/10.1002/med.21715] [PMID: 32687230] 
[14] 
Makhaeva, G.F.; Shevtsova, E.F.; Boltneva, N.P.; Lushchekina, S.V.; Kovaleva, N.V.; Rudakova, E.V.; Bachurin, S.O.; Richardson, R.J. Overview of novel multifunctional agents based on conjugates of γ-carbolines, carbazoles, tetrahydrocarbazoles, phenothiazines, and aminoadamantanes for treatment of Alzheimer’s disease. Chem. Biol. Interact.,  2019, 308, 224-234.
[http://dx.doi.org/10.1016/j.cbi.2019.05.020] [PMID: 31100279] 
[15] 
Van Giau, V.; An, S.S.A.; Hulme, J.P. Mitochondrial therapeutic interventions in Alzheimer’s disease. J. Neurol. Sci.,  2018, 395, 62-70.
[http://dx.doi.org/10.1016/j.jns.2018.09.033] [PMID: 30292965] 
[16] 
Hane, F.T.; Robinson, M.; Lee, B.Y.; Bai, O.; Leonenko, Z.; Albert, M.S. Recent progress in Alzheimer’s disease research, part 3: Diagnosis and treatment. J. Alzheimers Dis.,  2017, 57(3), 645-665.
[http://dx.doi.org/10.3233/JAD-160907] [PMID: 28269772] 
[17] 
Sochocka, M.; Donskow-Łysoniewska, K.; Diniz, B.S.; Kurpas, D.; Brzozowska, E.; Leszek, J. The gut microbiome alterations and inflammation-driven pathogenesis of Alzheimer’s disease - a critical review. Mol. Neurobiol.,  2019, 56(3), 1841-1851.
[http://dx.doi.org/10.1007/s12035-018-1188-4] [PMID: 29936690] 
[18] 
Mucke, L.; Masliah, E.; Yu, G.Q.; Mallory, M.; Rockenstein, E.M.; Tatsuno, G.; Hu, K.; Kholodenko, D.; Johnson-Wood, K.; McConlogue, L. High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: Synaptotoxicity without plaque formation. J. Neurosci.,  2000, 20(11), 4050-4058.
[http://dx.doi.org/10.1523/JNEUROSCI.20-11-04050.2000] [PMID: 10818140] 
[19] 
Chen, X.Q.; Mobley, W.C. Alzheimer disease pathogenesis: Insights from molecular and cellular biology studies of oligomeric Aβ and tau species. Front. Neurosci.,  2019, 13, 659.
[http://dx.doi.org/10.3389/fnins.2019.00659] [PMID: 31293377] 
[20] 
Vaz, M.; Silvestre, S. Alzheimer’s disease: Recent treatment strategies. Eur. J. Pharmacol.,  2020, 887, 173554.
[http://dx.doi.org/10.1016/j.ejphar.2020.173554] [PMID: 32941929] 
[21] 
Penke, B.; Szűcs, M.; Bogár, F. Oligomerization and conformational change turn monomeric β-amyloid and tau proteins toxic: Their role in Alzheimer’s pathogenesis. Molecules,  2020, 25(7), 1659.
[http://dx.doi.org/10.3390/molecules25071659] [PMID: 32260279] 
[22] 
Xin, S.H.; Tan, L.; Cao, X.; Yu, J.T.; Tan, L. Clearance of amyloid beta and tau in Alzheimer’s disease: From mechanisms to therapy. Neurotox. Res.,  2018, 34(3), 733-748.
[http://dx.doi.org/10.1007/s12640-018-9895-1] [PMID: 29626319] 
[23] 
Soria Lopez, J.A.; González, H.M.; Léger, G.C. Alzheimer’s disease. Handb. Clin. Neurol.,  2019, 167, 231-255.
[http://dx.doi.org/10.1016/B978-0-12-804766-8.00013-3] [PMID: 31753135] 
[24] 
Sun, B.L.; Li, W.W.; Zhu, C.; Jin, W.S.; Zeng, F.; Liu, Y.H.; Bu, X.L.; Zhu, J.; Yao, X.Q.; Wang, Y.J. Clinical research on Alzheimer’s disease: Progress and perspectives. Neurosci. Bull.,  2018, 34(6), 1111-1118.
[http://dx.doi.org/10.1007/s12264-018-0249-z] [PMID: 29956105] 
[25] 
Willem, M.; Garratt, A.N.; Novak, B.; Citron, M.; Kaufmann, S.; Rittger, A.; DeStrooper, B.; Saftig, P.; Birchmeier, C.; Haass, C. Control of peripheral nerve myelination by the beta-secretase BACE1. Science,  2006, 314(5799), 664-666.
[http://dx.doi.org/10.1126/science.1132341] [PMID: 16990514] 
[26] 
Panza, F.; Lozupone, M.; Solfrizzi, V.; Sardone, R.; Piccininni, C.; Dibello, V.; Stallone, R.; Giannelli, G.; Bellomo, A.; Greco, A.; Daniele, A.; Seripa, D.; Logroscino, G.; Imbimbo, B.P. BACE inhibitors in clinical development for the treatment of Alzheimer’s disease. Expert Rev. Neurother.,  2018, 18(11), 847-857.
[http://dx.doi.org/10.1080/14737175.2018.1531706] [PMID: 30277096] 
[27] 
Mikulca, J.A.; Nguyen, V.; Gajdosik, D.A.; Teklu, S.G.; Giunta, E.A.; Lessa, E.A.; Tran, C.H.; Terak, E.C.; Raffa, R.B. Potential novel targets for Alzheimer pharmacotherapy: II. Update on secretase inhibitors and related approaches. J. Clin. Pharm. Ther.,  2014, 39(1), 25-37.
[http://dx.doi.org/10.1111/jcpt.12112] [PMID: 24313554] 
[28] 
Godyń, J.; Jończyk, J.; Panek, D.; Malawska, B. Therapeutic strategies for Alzheimer’s disease in clinical trials. Pharmacol. Rep.,  2016, 68(1), 127-138.
[http://dx.doi.org/10.1016/j.pharep.2015.07.006] [PMID: 26721364] 
[29] 
Hsu, C.K.; Hsu, C.C.; Lee, J.Y.; Kuo, Y.M.; Pai, M.C. Exacerbation of psoriatic skin lesions in a patient with Alzheimer disease receiving gamma-secretase inhibitor. J. Am. Acad. Dermatol.,  2013, 68(2), e46-e48.
[http://dx.doi.org/10.1016/j.jaad.2012.07.012] [PMID: 23317986] 
[30] 
Wischik, C.M.; Edwards, P.C.; Lai, R.Y.; Roth, M.; Harrington, C.R. Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines. Proc. Natl. Acad. Sci. USA,  1996, 93(20), 11213-11218.
[http://dx.doi.org/10.1073/pnas.93.20.11213] [PMID: 8855335] 
[31] 
Liu, Y.; Cong, L.; Han, C.; Li, B.; Dai, R. Recent Progress in the Drug development for the treatment of Alzheimer’s disease especially on inhibition of amyloid-peptide aggregation. Mini Rev. Med. Chem.,  2021, 21(8), 969-990.
[http://dx.doi.org/10.2174/1389557520666201127104539] [PMID: 33245270] 
[32] 
Serenó, L.; Coma, M.; Rodríguez, M.; Sánchez-Ferrer, P.; Sánchez, M.B.; Gich, I.; Agulló, J.M.; Pérez, M.; Avila, J.; Guardia-Laguarta, C.; Clarimón, J.; Lleó, A.; Gómez-Isla, T. A novel GSK-3beta inhibitor reduces Alzheimer’s pathology and rescues neuronal loss in vivo. Neurobiol. Dis.,  2009, 35(3), 359-367.
[http://dx.doi.org/10.1016/j.nbd.2009.05.025] [PMID: 19523516] 
[33] 
Matsunaga, S.; Fujishiro, H.; Takechi, H. Efficacy and safety of glycogen synthase kinase 3 inhibitors for Alzheimer’s disease: A systematic review and meta-analysis. J. Alzheimers Dis.,  2019, 69(4), 1031-1039.
[http://dx.doi.org/10.3233/JAD-190256] [PMID: 31156177] 
[34] 
Congdon, E.E.; Wu, J.W.; Myeku, N.; Figueroa, Y.H.; Herman, M.; Marinec, P.S.; Gestwicki, J.E.; Dickey, C.A.; Yu, W.H.; Duff, K.E. Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo. Autophagy,  2012, 8(4), 609-622.
[http://dx.doi.org/10.4161/auto.19048] [PMID: 22361619] 
[35] 
Baddeley, T.C.; McCaffrey, J.; Storey, J.M.; Cheung, J.K.; Melis, V.; Horsley, D.; Harrington, C.R.; Wischik, C.M. Complex disposition of methylthioninium redox forms determines efficacy in tau aggregation inhibitor therapy for Alzheimer’s disease. J. Pharmacol. Exp. Ther.,  2015, 352(1), 110-118.
[http://dx.doi.org/10.1124/jpet.114.219352] [PMID: 25320049] 
[36] 
Wilcock, G.K.; Gauthier, S.; Frisoni, G.B.; Jia, J.; Hardlund, J.H.; Moebius, H.J.; Bentham, P.; Kook, K.A.; Schelter, B.O.; Wischik, D.J.; Davis, C.S.; Staff, R.T.; Vuksanovic, V.; Ahearn, T.; Bracoud, L.; Shamsi, K.; Marek, K.; Seibyl, J.; Riedel, G.; Storey, J.M.D.; Harrington, C.R.; Wischik, C.M. Potential of low dose leuco-methylthioninium Bis(Hydromethanesulphonate) (LMTM) monotherapy for treatment of mild Alzheimer’s disease: Cohort analysis as modified primary outcome in a phase III clinical trial. J. Alzheimers Dis.,  2018, 61(1), 435-457.
[http://dx.doi.org/10.3233/JAD-170560] [PMID: 29154277] 
[37] 
Barbier, P.; Zejneli, O.; Martinho, M.; Lasorsa, A.; Belle, V.; Smet-Nocca, C.; Tsvetkov, P.O.; Devred, F.; Landrieu, I. Role of tau as a microtubule-associated protein: Structural and functional aspects. Front. Aging Neurosci.,  2019, 11, 204.
[http://dx.doi.org/10.3389/fnagi.2019.00204] [PMID: 31447664] 
[38] 
Morimoto, B.H.; Schmechel, D.; Hirman, J.; Blackwell, A.; Keith, J.; Gold, M. A double-blind, placebo-controlled, ascending-dose, randomized study to evaluate the safety, tolerability and effects on cognition of AL-108 after 12 weeks of intranasal administration in subjects with mild cognitive impairment. Dement. Geriatr. Cogn. Disord.,  2013, 35(5-6), 325-336.
[http://dx.doi.org/10.1159/000348347] [PMID: 23594991] 
[39] 
Panza, F.; Lozupone, M.; Seripa, D.; Imbimbo, B.P. Amyloid-β immunotherapy for alzheimer disease: Is it now a long shot? Ann. Neurol.,  2019, 85(3), 303-315.
[http://dx.doi.org/10.1002/ana.25410] [PMID: 30635926] 
[40] 
Panza, F.; Logroscino, G.; Imbimbo, B.P.; Solfrizzi, V. Is there still any hope for amyloid-based immunotherapy for Alzheimer’s disease? Curr. Opin. Psychiatry,  2014, 27(2), 128-137.
[http://dx.doi.org/10.1097/YCO.0000000000000041] [PMID: 24445401] 
[41] 
Lopez Lopez, C.; Tariot, P.N.; Caputo, A.; Langbaum, J.B.; Liu, F.; Riviere, M.E.; Langlois, C.; Rouzade-Dominguez, M.L.; Zalesak, M.; Hendrix, S.; Thomas, R.G.; Viglietta, V.; Lenz, R.; Ryan, J.M.; Graf, A.; Reiman, E.M. The Alzheimer’s Prevention Initiative Generation Program: Study design of two randomized controlled trials for individuals at risk for clinical onset of Alzheimer’s disease. Alzheimers Dement. (N. Y.),  2019, 5, 216-227.
[http://dx.doi.org/10.1016/j.trci.2019.02.005] [PMID: 31211217] 
[42] 
Winblad, B.; Graf, A.; Riviere, M.E.; Andreasen, N.; Ryan, J.M. Active immunotherapy options for Alzheimer’s disease. Alzheimers Res. Ther.,  2014, 6(1), 7.
[http://dx.doi.org/10.1186/alzrt237] [PMID: 24476230] 
[43] 
Lannfelt, L.; Relkin, N.R.; Siemers, E.R. Amyloid-ß-directed immunotherapy for Alzheimer’s disease. J. Intern. Med.,  2014, 275(3), 284-295.
[http://dx.doi.org/10.1111/joim.12168] [PMID: 24605809] 
[44] 
Panza, F.; Solfrizzi, V.; Imbimbo, B.P.; Tortelli, R.; Santamato, A.; Logroscino, G. Amyloid-based immunotherapy for Alzheimer’s disease in the time of prevention trials: The way forward. Expert Rev. Clin. Immunol.,  2014, 10(3), 405-419.
[http://dx.doi.org/10.1586/1744666X.2014.883921] [PMID: 24490853] 
[45] 
Loureiro, J.C.; Pais, M.V.; Stella, F.; Radanovic, M.; Teixeira, A.L.; Forlenza, O.V.; de Souza, L.C. Passive antiamyloid immunotherapy for Alzheimer’s disease. Curr. Opin. Psychiatry,  2020, 33(3), 284-291.
[http://dx.doi.org/10.1097/YCO.0000000000000587] [PMID: 32040044] 
[46] 
Bittar, A.; Bhatt, N.; Kayed, R. Advances and considerations in AD tau-targeted immunotherapy. Neurobiol. Dis.,  2020, 134, 104707.
[http://dx.doi.org/10.1016/j.nbd.2019.104707] [PMID: 31841678] 
[47] 
Theunis, C.; Crespo-Biel, N.; Gafner, V.; Pihlgren, M.; López-Deber, M.P.; Reis, P.; Hickman, D.T.; Adolfsson, O.; Chuard, N.; Ndao, D.M.; Borghgraef, P.; Devijver, H.; Van Leuven, F.; Pfeifer, A.; Muhs, A. Efficacy and safety of a liposome-based vaccine against protein Tau, assessed in tau.P301L mice that model tauopathy. PLoS One,  2013, 8(8), e72301.
[http://dx.doi.org/10.1371/journal.pone.0072301] [PMID: 23977276] 
[48] 
Castillo-Carranza, D.L.; Guerrero-Muñoz, M.J.; Sengupta, U.; Hernandez, C.; Barrett, A.D.; Dineley, K.; Kayed, R. Tau immunotherapy modulates both pathological tau and upstream amyloid pathology in an Alzheimer’s disease mouse model. J. Neurosci.,  2015, 35(12), 4857-4868.
[http://dx.doi.org/10.1523/JNEUROSCI.4989-14.2015] [PMID: 25810517] 
[49] 
Umeda, T.; Eguchi, H.; Kunori, Y.; Matsumoto, Y.; Taniguchi, T.; Mori, H.; Tomiyama, T. Passive immunotherapy of tauopathy targeting pSer413-tau: A pilot study in mice. Ann. Clin. Transl. Neurol.,  2015, 2(3), 241-255.
[http://dx.doi.org/10.1002/acn3.171] [PMID: 25815351] 
[50] 
Krishnaswamy, S.; Lin, Y.; Rajamohamedsait, W.J.; Rajamohamedsait, H.B.; Krishnamurthy, P.; Sigurdsson, E.M. Antibody-derived in vivo imaging of tau pathology. J. Neurosci.,  2014, 34(50), 16835-16850.
[http://dx.doi.org/10.1523/JNEUROSCI.2755-14.2014] [PMID: 25505335] 
[51] 
Giacobini, E.; Gold, G. Alzheimer disease therapy-moving from amyloid-β to tau. Nat. Rev. Neurol.,  2013, 9(12), 677-686.
[http://dx.doi.org/10.1038/nrneurol.2013.223] [PMID: 24217510] 
[52] 
Wang, X.; Sun, G.; Feng, T.; Zhang, J.; Huang, X.; Wang, T.; Xie, Z.; Chu, X.; Yang, J.; Wang, H.; Chang, S.; Gong, Y.; Ruan, L.; Zhang, G.; Yan, S.; Lian, W.; Du, C.; Yang, D.; Zhang, Q.; Lin, F.; Liu, J.; Zhang, H.; Ge, C.; Xiao, S.; Ding, J.; Geng, M. Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression. Cell Res.,  2019, 29(10), 787-803.
[http://dx.doi.org/10.1038/s41422-019-0216-x] [PMID: 31488882] 
[53] 
Lu, M.; Liu, T.; Jiao, Q.; Ji, J.; Tao, M.; Liu, Y.; You, Q.; Jiang, Z. Discovery of a Keap1-dependent peptide PROTAC to knockdown Tau by ubiquitination-proteasome degradation pathway. Eur. J. Med. Chem.,  2018, 146, 251-259.
[http://dx.doi.org/10.1016/j.ejmech.2018.01.063] [PMID: 29407955] 
[54] 
Chu, T.T.; Gao, N.; Li, Q.Q.; Chen, P.G.; Yang, X.F.; Chen, Y.X.; Zhao, Y.F.; Li, Y.M. Specific knockdown of endogenous tau protein by peptide-directed ubiquitin-proteasome degradation. Cell Chem. Biol.,  2016, 23(4), 453-461.
[http://dx.doi.org/10.1016/j.chembiol.2016.02.016] [PMID: 27105281] 
[55] 
Wang, W.; Zhou, Q.; Jiang, T.; Li, S.; Ye, J.; Zheng, J.; Wang, X.; Liu, Y.; Deng, M.; Ke, D.; Wang, Q.; Wang, Y.; Wang, J.Z. A novel small-molecule PROTAC selectively promotes tau clearance to improve cognitive functions in Alzheimer-like models. Theranostics,  2021, 11(11), 5279-5295.
[http://dx.doi.org/10.7150/thno.55680] [PMID: 33859747] 
[56] 
Barros-Viegas, A.T.; Carmona, V.; Ferreiro, E.; Guedes, J.; Cardoso, A.M.; Cunha, P.; Pereira de Almeida, L.; Resende de Oliveira, C.; Pedro de Magalhães, J.; Peça, J.; Cardoso, A.L. miRNA-31 improves cognition and abolishes amyloid-β pathology by targeting APP and BACE1 in an animal model of Alzheimer’s disease. Mol. Ther. Nucleic Acids,  2020, 19, 1219-1236.
[http://dx.doi.org/10.1016/j.omtn.2020.01.010] [PMID: 32069773] 
[57] 
Zhou, Y.; Zhu, F.; Liu, Y.; Zheng, M.; Wang, Y.; Zhang, D.; Anraku, Y.; Zou, Y.; Li, J.; Wu, H.; Pang, X.; Tao, W.; Shimoni, O.; Bush, A.I.; Xue, X.; Shi, B. Blood-brain barrier-penetrating siRNA nanomedicine for Alzheimer’s disease therapy. Sci. Adv.,  2020, 6(41), eabc7031.
[http://dx.doi.org/10.1126/sciadv.abc7031] [PMID: 33036977] 
[58] 
Li, Q.; Liu, Y.; Sun, M. Autophagy and Alzheimer’s disease. Cell. Mol. Neurobiol.,  2017, 37(3), 377-388.
[http://dx.doi.org/10.1007/s10571-016-0386-8] [PMID: 27260250] 
[59] 
Darreh-Shori, T.; Rezaeianyazdi, S.; Lana, E.; Mitra, S.; Gellerbring, A.; Karami, A.; Bogdanovic, N.; Lithner, C.U.; Winblad, B.; Behbahani, H. Increased active OMI/HTRA2 serine protease displays a positive correlation with cholinergic alterations in the Alzheimer’s disease brain. Mol. Neurobiol.,  2019, 56(7), 4601-4619.
[http://dx.doi.org/10.1007/s12035-018-1383-3] [PMID: 30361890] 
[60] 
Pattingre, S.; Bauvy, C.; Levade, T.; Levine, B.; Codogno, P. Ceramide-induced autophagy: To junk or to protect cells? Autophagy,  2009, 5(4), 558-560.
[http://dx.doi.org/10.4161/auto.5.4.8390] [PMID: 19337026] 
[61] 
Gao, J.; Chen, X.; Ma, T.; He, B.; Li, P.; Zhao, Y.; Ma, Y.; Zhuang, J.; Yin, Y. PEG-ceramide nanomicelles induce autophagy and degrade tau proteins in N2a cells. Int. J. Nanomedicine,  2020, 15, 6779-6789.
[http://dx.doi.org/10.2147/IJN.S258311] [PMID: 32982233] 
[62] 
Pardridge, W.M. Treatment of Alzheimer’s disease and blood-brain barrier drug delivery. Pharmaceuticals (Basel),  2020, 13(11), 394.
[http://dx.doi.org/10.3390/ph13110394] [PMID: 33207605] 
[63] 
Ma, T.J.; Gao, J.; Liu, Y.; Zhuang, J.H.; Yin, C.; Li, P.; Mao, L.; Xu, J.; Xu, Y.X.; Li, Y.P.; Zhao, Z.X.; Yin, Y. Nanomedicine strategies for sustained, controlled and targeted treatment of Alzheimer’s disease. Mini Rev. Med. Chem.,  2018, 18(12), 1035-1046.
[http://dx.doi.org/10.2174/1389557518666171215150024] [PMID: 29243575] 
[64] 
Parhi, P.; Mohanty, C.; Sahoo, S.K. Nanotechnology-based combinational drug delivery: An emerging approach for cancer therapy. Drug Discov. Today,  2012, 17(17-18), 1044-1052.
[http://dx.doi.org/10.1016/j.drudis.2012.05.010] [PMID: 22652342] 
[65] 
Breijyeh, Z.; Karaman, R. Comprehensive review on alzheimer’s disease: causes and treatment. Molecules,  2020, 25(24), 5789.
[PMID: 33302541] 

Rights & Permissions Print Cite

Article Metrics

19

1

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1389557522666220214092824	Print ISSN 1389-5575
Publisher Name Bentham Science Publisher	Online ISSN 1875-5607

Mini-Reviews in Medicinal Chemistry

Recent Advancements in Strategies for Abnormal Protein Clearance in Alzheimer's Disease

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Abstract