Emerging therapeutics and future insights into the pathobiology of Alzheimer’s disease
Paper Details
Emerging therapeutics and future insights into the pathobiology of Alzheimer’s disease
Abstract
Alzheimer’s disease (AD) is a complex neurodegenerative disorder that involves progressive memory loss and brain atrophy due to deregulated neurobiological networks. Despite decades of intense research, therapies for AD are still in development, and the results of several ongoing pivotal clinical trials are anticipated. Because many recent amyloid-β (Aβ)-targeting therapies have failed, the amyloid hypothesis and alternative clinical strategies need to be reinvestigated. In addition to Aβ inhibition, the inhibition of the hyper-phosphorylation of tau, which is a downstream target of kinases and signaling cascades, is a potential therapeutic strategy. In this review, we discuss current AD treatment strategies that utilize small-molecule therapies that aim to inhibit Aβ accumulation or tau phosphorylation. We then present a comprehensive and balanced overview of recently discovered immunological pathways that make this disease more complex. Targeting these potential pathways will shape future therapeutic approaches in AD.
Aisen PS, Gauthier S, Vellas B, Briand R, Saumier D, Laurin J, Garceau D. 2007. Alzhemed: a potential treatment for Alzheimers disease. Current Alzheimer Research 4, 473-478.
Andrade Nunes M, Araujo Viel T, Sousa Buck H. 2013. Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer’s disease. Current Alzheimer Research 10, 104-107.
Benilova I, De Strooper B. 2013. Promiscuous Alzheimer’s Amyloid: Yet Another Partner. Science 341, 1354-1355.
Bhat R, Xue Y, Berg S, Hellberg S, Ormö M, Nilsson Y, Radesäter AC, Jerning E, Markgren PO, Borgegård T. 2003. Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418. Journal of Biological Chemistry278, 45937-45945.
Branca C, Sarnico I, Ruotolo R, Lanzillotta A, Viscomi AR, Benarese M, Porrini V, Lorenzini L, Calzà L, Imbimbo BP. 2014. Pharmacological targeting of the β-amyloid precursor protein intracellular domain. Scientific reports4.
Burden AC. 2011. The costs of Alzheimer’s disease and the value of effective therapies. The American Journal of Managed Care 17, S356-S362.
Chiti F, Dobson CM. 2006. Protein misfolding, functional amyloid, and human disease. Annual Review of Biochemistry 75, 333-366.
Cole SL, Vassar R. 2008. The role of amyloid precursor protein processing by BACE1, the β-secretase, in Alzheimer disease pathophysiology. Journal of Biological Chemistry 283, 29621-29625.
Coric V, Van Dyck CH, Salloway S, Andreasen N, Brody M, Richter, RW, Soininen, H, Thein, S, Shiovitz T, Pilcher G. 2012. Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Archives of neurology 69, 1430-1440.
Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, Arbuckle M, Callaghan, M, Tsai E, Plymate SR. 2012. Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive ImpairmentA Pilot Clinical Trial. Archives of neurology 69, 29-38.
Crouch PJ, Savva MS, Hung LW, Donnelly PS, Mot AI, Parker SJ, Greenough MA, Volitakis, I, Adlard PA, Cherny RA. 2011. The Alzheimer’s therapeutic PBT2 promotes amyloid‐β degradation and GSK3 phosphorylation via a metal chaperone activity. Journal of neurochemistry119, 220-230.
Cruz JC, Tsai LH. 2004. Cdk5 deregulation in the pathogenesis of Alzheimer’s disease. Trends in molecular medicine10, 452-458.
De Strooper B. 2014. Lessons from a failed γ-secretase Alzheimer trial. Cell 159, 721-726.
Del Ser T, Steinwachs KC, Gertz HJ, Andrés, MV, Gómez-Carrillo, B, Medina, M, Vericat, JA, Redondo P, Fleet D, León T. 2013. Treatment of Alzheimer’s disease with the GSK-3 inhibitor tideglusib: a pilot study. Journal of Alzheimer’s Disease 33, 205-215.
Djurisic M, Vidal GS, Mann M, Aharon A, Kim, T, Santos AF, Zuo Y, Hübener M, Shatz CJ. 2013. PirB regulates a structural substrate for cortical plasticity. Proceedings of the National Academy of Sciences110, 20771-20776.
Dodel R, Rominger A, Bartenstein P, Barkhof, F, Blennow K, Förster S, Winter Y, Bach JP, Popp J, Alferink J. 2013. Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer’s disease: a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial. The Lancet Neurology12, 233-243.
Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, He F, Sun X, Thomas, RG. 2013. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. New England Journal of Medicine 369, 341-350.
Finan GM, Okada H, Kim TW. 2011. BACE1 retrograde trafficking is uniquely regulated by the cytoplasmic domain of sortilin. Journal of Biological Chemistry286, 12602-12616.
Froestl W, Gallagher M, Jenkins H, Madrid A, Melcher T, Teichman S, Mondadori CG, Pearlman R. 2004. SGS742: the first GABA< sub> B</sub> receptor antagonist in clinical trials. Biochemical pharmacology 68, 1479-1487.
Griffin WST. 2013. Neuroinflammatory cytokine signaling and Alzheimer’s disease. New England Journal of Medicine368, 770-771.
Haass C, Kaether C, Thinakaran G, Sisodia S. 2012. Trafficking and proteolytic processing of APP. Cold Spring Harbor perspectives in medicine2.
He G, Luo W, Li P, Remmers C, Netzer WJ, Hendrick J, Bettayeb K, Flajolet M, Gorelick F, Wennogle LP. 2010. Gamma-secretase activating protein is a therapeutic target for Alzheimer/’s disease. Nature 467, 95-98.
Huang Y, Mucke L. 2012. Alzheimer mechanisms and therapeutic strategies. Cell 148, 1204-1222.
Hung SY, Fu WM. 2017. Drug candidates in clinical trials for Alzheimer’s disease. Journal of Biomedical Science24, 47.
Hussain I, Hawkins J, Harrison D, Hille C, Wayne G, Cutler L, Buck T, Walter, D, Demont E, Howes C. 2007. Oral administration of a potent and selective non‐peptidic BACE‐1 inhibitor decreases β‐cleavage of amyloid precursor protein and amyloid‐β production in vivo. Journal of neurochemistry100, 802-809.
Jeppsson F, Eketjäll S, Janson J, Karlström S, Gustavsson S, Olsson LL, Radesäter AC, Ploeger B, Cebers G, Kolmodin K. 2012. Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of Alzheimer disease. Journal of Biological Chemistry287, 41245-41257.
Jia Q, Deng Y, Qing H. 2014. Potential therapeutic strategies for Alzheimer’s disease targeting or beyond β-amyloid: insights from clinical trials. BioMed research international 2014.
Kam TI, Song S, Gwon Y, Park H, Yan JJ, Im I, Choi, JW, Choi TY, Kim J, Song DK. 2013. FcγRIIb mediates amyloid-β neurotoxicity and memory impairment in Alzheimer’s disease. The Journal of clinical investigation 123, 2791.
Karran E, Mercken M, De Strooper B. 2011. The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nature Reviews Drug Discovery10, 698-712.
Kennedy ME, Stamford AW, Chen X, Cox K, Cumming JN, Dockendorf MF, Egan M, Ereshefsky L, Hodgson RA, Hyde LA. 2016. The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer’s disease patients. Science translational medicine 8, 363ra150-363ra150.
Konzack, S, Thies, E, Marx, A, Mandelkow, E-M, & Mandelkow, E. 2007. Swimming against the tide: mobility of the microtubule-associated protein tau in neurons. The Journal of neuroscience27, 9916-9927.
Kuhn PH, Wang H, Dislich B, Colombo A, Zeitschel U, Ellwart JW, Kremmer E, Roßner S, Lichtenthaler SF. 2010. ADAM10 is the physiologically relevant, constitutive α‐secretase of the amyloid precursor protein in primary neurons. The EMBO journal 29, 3020-3032.
Kumar A, Singh A. 2015. A review on Alzheimer’s disease pathophysiology and its management: an update. Pharmacological Reports67, 195-203.
Landen JW, Zhao Q, Cohen S, Borrie M, Woodward M, Billing Jr CB, Bales K, Alvey C, McCush F, Yang, J. 2013. Safety and pharmacology of a single intravenous dose of ponezumab in subjects with mild-to-moderate Alzheimer disease: a phase I, randomized, placebo-controlled, double-blind, dose-escalation study. Clinical neuropharmacology 36, 14-23.
Lannfelt L, Blennow K, Zetterberg H, Batsman S, Ames D, Harrison J, Masters CL, Targum S, Bush AI, Murdoch R. 2008. Safety, efficacy, and biomarker findings of PBT2 in targeting Aβ as a modifying therapy for Alzheimer’s disease: a phase IIa, double-blind, randomised, placebo-controlled trial. The Lancet Neurology7, 779-786.
Lehnardt S. 2010. Innate immunity and neuroinflammation in the CNS: The role of microglia in Toll‐like receptor‐mediated neuronal injury. Glia58, 253-263.
Liu SL, Wang C, Jiang T, Tan L, Xing A, Yu, JT. 2016. The role of Cdk5 in Alzheimer’s disease. Molecular neurobiology 53, 4328-4342.
Liu X, Zhao X, Zeng X, Bossers K, Swaab DF, Zhao J, Pei G. 2013. β-Arrestin1 regulates γ-secretase complex assembly and modulates amyloid-β pathology. Cell research 23, 351-365.
Makin OS, Serpell LC. 2005. Structures for amyloid fibrils. Febs JournalN272, 5950-5961.
Matsuoka Y, Jouroukhin Y, Gray AJ, Ma L, Hirata-Fukae C, Li HF, Feng L, Lecanu L, Walker BR, Planel E. 2008. A neuronal microtubule-interacting agent, NAPVSIPQ, reduces tau pathology and enhances cognitive function in a mouse model of Alzheimer’s disease. Journal of Pharmacology and Experimental Therapeutics325, 146-153.
May PC, Dean RA, Lowe SL, Martenyi F, Sheehan SM, Boggs LN, Monk SA, Mathes BM, Mergott DJ, Watson BM. 2011. Robust central reduction of amyloid-β in humans with an orally available, non-peptidic β-secretase inhibitor. Journal of Neuroscience31, 16507-16516.
Mucke L, Selkoe DJ. 2012. Neurotoxicity of amyloid β-protein: synaptic and network dysfunction. Cold Spring Harbor perspectives in medicine2.
Ni Y, Zhao X, Bao G, Zou L, Teng L, Wang Z, Song M, Xiong J, Bai Y, Pei, G. 2006. Activation of β2-adrenergic receptor stimulates γ-secretase activity and accelerates amyloid plaque formation. Nature medicine12, 1390-1396.
Orgogozo JM, Gilman S, Dartigues JF, Laurent B, Puel M, Kirby L, Jouanny P, Dubois B, Eisner L, Flitman S. 2003. Subacute meningoencephalitis in a subset of patients with AD after Aβ42 immunization. Neurology61, 46-54.
Panza F, Solfrizzi V, Imbimbo BP, Tortelli R, Santamato A, Logroscino G. 2014. Amyloid-based immunotherapy for Alzheimer’s disease in the time of prevention trials: the way forward. Expert review of clinical immunology10, 405-419.
Panza F, Solfrizzi V, Seripa D, Imbimbo BP, Lozupone M, Santamato A, Zecca C, Barulli, MR, Bellomo A, Pilotto A. 2016. Tau-centric targets and drugs in clinical development for the treatment of Alzheimer’s disease. BioMed research international2016.
Rafii MS. 2013. Update on Alzheimer’s disease therapeutics. Reviews on recent clinical trials8, 110-118.
Salloway S, Sperling R, Gilman S, Fox N, Blennow K, Raskind M, Sabbagh M, Honig L, Doody R, Van Dyck C. 2009. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology73, 2061-2070.
Salloway S, Sperling R, Keren R, Porsteinsson A, Van Dyck C, Tariot P, Gilman S, Arnold D, Abushakra S, Hernandez C. 2011. A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease. Neurology77, 1253-1262.
Schilling S, Zeitschel U, Hoffmann T, Heiser U, Francke M, Kehlen A, Holzer M, Hutter Paier B, Prokesch M, Windisch M. 2008. Glutaminyl cyclase inhibition attenuates pyroglutamate Aβ and Alzheimer’s disease–like pathology. Nature medicine14, 1106-1111.
Shahani N, Pryor W, Swarnkar S, Kholodilov, N, Thinakaran G, Burke RE, Subramaniam S. 2013. Rheb GTPase Regulates β-Secretase Levels and Amyloid β Generation. Journal of Biological Chemistry, jbc. M113. 532713.
Sivilia S, Lorenzini L, Giuliani A, Gusciglio M, Fernandez M, Baldassarro VA, Mangano C, Ferraro L, Pietrini V, Baroc MF. 2013. Multi-target action of the novel anti-Alzheimer compound CHF5074: in vivo study of long term treatment in Tg2576 mice. BMC Neurosci14, 44.
Tajes M, Gutierrez-Cuesta J, Folch J, Ferrer I, Caballero B, Smith MA, Casadesus G, Camins, A, Pallás M. 2008. Lithium treatment decreases activities of tau kinases in a murine model of senescence. Journal of Neuropathology & Experimental Neurology67, 612-623.
Thathiah A, Horré K, Snellinx A, Vandewyer E, Huang Y, Ciesielska M, De Kloe G, Munck, S, De Strooper B. 2013. [beta]-arrestin 2 regulates A [beta] generation and [gamma]-secretase activity in Alzheimer’s disease. Nature medicine 19, 43-49.
Thathiah A, Spittaels K, Hoffmann M, Staes M, Cohen A, Horré K, Vanbrabant M, Coun, F, Baekelandt V, Delacourte A. 2009. The orphan G protein–coupled receptor 3 modulates amyloid-beta peptide generation in neurons. Science323, 946-951.
Vellas B, Sol OJ, Snyder P, Ousset PJ, Haddad R, Maurin M, Lemarié JC, Désiré L, Pando PM. 2011. EHT0202 in Alzheimer’s disease: a 3-month, randomized, placebo-controlled, double-blind study. Current Alzheimer Research8, 203-212.
vom Berg J, Prokop S, Miller KR, Obst J, Kälin RE, Lopategui-Cabezas I, Wegner A, Mair F, Schipke CG, Peters O. 2012. Inhibition of IL-12/IL-23 signaling reduces Alzheimer’s disease-like pathology and cognitive decline. Nature medicine18, 1812-1819.
Walters A, Phillips E, Zheng R, Biju M, Kuruvilla T. 2016. Evidence for neuroinflammation in Alzheimer’s disease. Progress in Neurology and Psychiatry20, 25-31.
Wen Y, Planel E, Herman M, Figueroa HY, Wang L, Liu L, Lau LF, Yu WH, Duff KE. 2008. Interplay between cyclin-dependent kinase 5 and glycogen synthase kinase 3β mediated by neuregulin signaling leads to differential effects on tau phosphorylation and amyloid precursor protein processing. The Journal of neuroscience 28, 2624-2632.
Wiessner C, Wiederhold KH, Tissot AC, Frey P, Danner S, Jacobson LH, Jennings GT, Lüönd R, Ortmann R, Reichwald J. 2011. The second-generation active Aβ immunotherapy CAD106 reduces amyloid accumulation in APP transgenic mice while minimizing potential side effects. Journal of Neuroscience31, 9323-9331.
Wilcock GK, Black SE, Hendrix SB, Zavitz, KH, Swabb EA, Laughlin MA. 2008. Efficacy and safety of tarenflurbil in mild to moderate Alzheimer’s disease: a randomised phase II trial. The Lancet Neurology 7, 483-493.
Wilkinson BL, Cramer PE, Varvel NH, Reed Geaghan E, Jiang Q, Szabo A, Herrup K, Lamb BT, Landreth GE. 2012. Ibuprofen attenuates oxidative damage through NOX2 inhibition in Alzheimer’s disease. Neurobiology of aging 33, 197. e121-197. e132.
Xu Y, Chen Y, Zhang P, Jeffrey PD, Shi Y. 2008. Structure of a protein phosphatase 2A holoenzyme: insights into B55-mediated Tau dephosphorylation. Molecular cell31, 873-885.
Zhang B, Carroll J, Trojanowski JQ, Yao Y, Iba M, Potuzak JS, Hogan AML, Xie SX, Ballatore, C, Smith AB. 2012. The microtubule-stabilizing agent, epothilone D, reduces axonal dysfunction, neurotoxicity, cognitive deficits, and Alzheimer-like pathology in an interventional study with aged tau transgenic mice. The Journal of neuroscience32, 3601-3611.
Zhang X, Li F, Bulloj A, Zhang Yw, Tong G, Zhang Z, Liao, FF, Xu H. 2006. Tumor-suppressor PTEN affects tau phosphorylation, aggregation, and binding to microtubules. The FASEB journal 20, 1272-1274.
Zhao Y, Wang Y, Yang J, Wang X, Zhang X, Zhang Y. 2012. Sorting nexin 12 interacts with BACE1 and regulates BACE1-mediated APP processing. Mol Neurodegeneration 7, 30.
Zhou M, Cui Zl, Guo XJ, Ren LP, Yang M, Fan ZW, Han RC, XU WG. 2015. Blockade of Notch signalling by γ-secretase inhibitor in lung T cells of asthmatic mice affects T cell differentiation and pulmonary inflammation. Inflammation 38, 1281-1288.
Zhu A, Xi A, Li G, Li Y, Liao B, Zhong X, Zhou J, Gu S, Yu M, Chu Y. 2012. Ratanasampil (Tibetan Medicine, RNSP) Reduces β-Amyloid Protein (Aβ) and Pro-Inflammatory Factor Levels and Improves Cognitive Functions in Mild-to-Moderate Alzheimer’s Disease (AD) Patients Living at High Altitude. Journal of Behavioral and Brain Science 2, 82.
Irfan Ullah, Sang-Kyung Lee (2018), Emerging therapeutics and future insights into the pathobiology of Alzheimer’s disease; IJB, V12, N2, February, P231-246
https://innspub.net/emerging-therapeutics-and-future-insights-into-the-pathobiology-of-alzheimers-disease/
Copyright © 2018
By Authors and International
Network for Natural Sciences
(INNSPUB) https://innspub.net
This article is published under the terms of the
Creative Commons Attribution License 4.0