Abstract
Alzheimer’s disease (AD) is a progressively neurodegenerative disease that eventually leads to the irreversible loss of neurons and intellectual abilities, including cognition and memory. AD has become the most common cause of dementia in aged people, and the ill-defined pathogenesis of AD is seriously impeding the current drug discovery against this disease. To date, there is still a lack of etiologically therapeutic drugs for AD, although some symptomatic treatments have been successfully developed. The β-amyloid (Aβ)-induced neurodegeneration is determined as the main pathogenesis of AD, and by targeting the regulation of Aβ in production inhibition or clearance promotion, many active agents have been designed potentially for AD treatment, but no drug has yet been approved in clinical use. Actually, AD has a complex pathogenic mechanism that involves multiple aberrant signaling genes and pathways, and the idea of ‘single target’ for anti-AD drug research is thus full of challenges. Recently, with a deep understanding of AD pathogeneses and the development of advanced pharmacological techniques, ‘multiple target’-based strategy has been widely applied for the drug discovery against this disease, and many promising results have been achieved. Here, we review the recent multitarget strategies for the drug discovery in the treatment of AD by focusing on the involvement of Aβ regulation.
Acknowledgments
This work was supported by the National Science & Technology Major Project (2012ZX09301001-004) and the National Natural Science Foundation of China (grants 81373462 and 81473141).
References
An, W.L., Cowburn, R.F., Li, L., Braak, H., Alafuzoff, I., Iqbal, K., Iqbal, I.G., Winblad, B., and Pei, J.J. (2003). Up-regulation of phosphorylated/activated p70 S6 kinase and its relationship to neurofibrillary pathology in Alzheimer’s disease. Am. J. Pathol. 163, 591–607.10.1016/S0002-9440(10)63687-5Search in Google Scholar
Ansari, N. and Khodagholi, F. (2013). Molecular mechanism aspect of ER stress in Alzheimer’s disease: current approaches and future strategies. Curr. Drug Targets 14, 114–122.10.2174/138945013804806532Search in Google Scholar
Bachurin, S., Bukatina, E., Lermontova, N., Tkachenko, S., Afanasiev, A., Grigoriev, V., Grigorieva, I., Ivanov, Y., Sablin, S., and Zefirov, N. (2001). Antihistamine agent Dimebon as a novel neuroprotector and a cognition enhancer. Ann. N. Y. Acad. Sci. 939, 425–435.10.1111/j.1749-6632.2001.tb03654.xSearch in Google Scholar
Bajda, M., Guzior, N., Ignasik, M., and Malawska, B. (2011). Multi-target-directed ligands in Alzheimer’s disease treatment. Curr. Med. Chem. 18, 4949–4975.10.2174/092986711797535245Search in Google Scholar
Balazy, M. and Nigam, S. (2003). Aging, lipid modifications and phospholipases – new concepts. Ageing Res. Rev. 2, 191–209.10.1016/S1568-1637(02)00065-XSearch in Google Scholar
Bell, R.D., Sagare, A.P., Friedman, A.E., Bedi, G.S., Holtzman, D.M., Deane, R., and Zlokovic, B.V. (2007). Transport pathways for clearance of human Alzheimer’s amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system. J. Cereb. Blood. Flow Metab. 27, 909–918.10.1038/sj.jcbfm.9600419Search in Google Scholar PubMed PubMed Central
Bezprozvanny, I. and Mattson, M.P. (2008). Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease. Trends Neurosci. 31, 454–463.10.1016/j.tins.2008.06.005Search in Google Scholar PubMed PubMed Central
Black, S.E., Doody, R., Li, H., McRae, T., Jambor, K.M., Xu, Y., Sun, Y., Perdomo, C.A., and Richardson, S. (2007). Donepezil preserves cognition and global function in patients with severe Alzheimer disease. Neurology 69, 459–469.10.1212/01.wnl.0000266627.96040.5aSearch in Google Scholar PubMed
Bokov, A., Chaudhuri, A., and Richardson, A. (2004). The role of oxidative damage and stress in aging. Mech. Ageing Dev. 125, 811–826.10.1016/j.mad.2004.07.009Search in Google Scholar PubMed
Bolea, I., Gella, A., Monjas, L., Perez, C., Rodriguez-Franco, M.I., Marco-Contelles, J., Samadi, A., and Unzeta, M, (2013). Multipotent, permeable drug ASS234 inhibits Abeta aggregation, possesses antioxidant properties and protects from Abeta-induced apoptosis in vitro. Curr. Alzheimer Res. 10, 797–808.10.2174/15672050113109990151Search in Google Scholar PubMed
Bolognesi, M.L., Cavalli, A., and Melchiorre, C. (2009). Memoquin: a multi-target-directed ligand as an innovative therapeutic opportunity for Alzheimer’s disease. Neurotherapeutics 6, 152–162.10.1016/j.nurt.2008.10.042Search in Google Scholar
Bolognesi, M.L., Simoni, E., Rosini, M., Minarini, A., Tumiatti, V., and Melchiorre, C. (2011). Multitarget-directed ligands: innovative chemical probes and therapeutic tools against Alzheimer’s disease. Curr. Top. Med. Chem. 11, 2797–2806.10.2174/156802611798184373Search in Google Scholar
Bove, J., Martinez-Vicente, M., and Vila, M. (2011). Fighting neurodegeneration with rapamycin: mechanistic insights. Nat. Rev. Neurosci. 12, 437–452.10.1038/nrn3068Search in Google Scholar
Brewer, G.J. (2000). Neuronal plasticity and stressor toxicity during aging. Exp. Gerontol. 35, 1165–1183.10.1016/S0531-5565(00)00121-2Search in Google Scholar
Buccafusco, J.J. and Terry, A.V., Jr. (2000). Multiple central nervous system targets for eliciting beneficial effects on memory and cognition. J. Pharmacol. Exp. Ther. 295, 438–446.Search in Google Scholar
Caccamo, A., Oddo, S., Billings, L.M., Green, K.N., Martinez-Coria, H., Fisher, A., and LaFerla, F.M. (2006). M1 receptors play a central role in modulating AD-like pathology in transgenic mice. Neuron 49, 671–682.10.1016/j.neuron.2006.01.020Search in Google Scholar
Caccamo, A., Majumder, S., Richardson, A., Strong, R., and Oddo, S. (2010). Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and tau: effects on cognitive impairments. J. Biol. Chem. 285, 13107–13120.10.1074/jbc.M110.100420Search in Google Scholar
Cai, Z., Zhao, Y., Yao, S., and Bin Zhao, B. (2011). Increases in beta-amyloid protein in the hippocampus caused by diabetic metabolic disorder are blocked by minocycline through inhibition of NF-kappaB pathway activation. Pharmacol. Rep. 63, 381–391.10.1016/S1734-1140(11)70504-7Search in Google Scholar
Cai, Z., Zhao, B., Li, K., Zhang, L., Li, C., Quazi, S.H., and Tan, Y. (2012). Mammalian target of rapamycin: a valid therapeutic target through the autophagy pathway for Alzheimer’s disease? J. Neurosci. Res. 90, 1105–1118.10.1002/jnr.23011Search in Google Scholar PubMed
Campbell, N.A. and Reece, J.B. (2002). Biology. San Francisco: Benjamin Cummings.Search in Google Scholar
Capurro, V., Busquet, P., Lopes, J.P., Bertorelli, R., Tarozzo, G., Bolognesi, M.L., Piomelli, D., Reggiani, A., and Cavalli, A. (2013). Pharmacological characterization of memoquin, a multi-target compound for the treatment of Alzheimer’s disease. PLoS One 8, e56870.10.1371/journal.pone.0056870Search in Google Scholar PubMed PubMed Central
Cavalli, A., Bolognesi, M.L., Capsoni, S., Andrisano, V., Bartolini, M., Margotti, E., Cattaneo, A., Recanatini, M., and Melchiorre, C. (2007). A small molecule targeting the multifactorial nature of Alzheimer’s disease. Angew. Chem. 46, 3689–3692.10.1002/anie.200700256Search in Google Scholar PubMed
Cavallucci, V., D’Amelio, M., and Cecconi, F. (2012). Abeta toxicity in Alzheimer’s disease. Mol. Neurobiol. 45, 366–378.10.1007/s12035-012-8251-3Search in Google Scholar
Chang, K.H., Yan, M.D., Yao, C.J., Lin, P.C., and Lai, G.M. (2013). Honokiol-induced apoptosis and autophagy in glioblastoma multiforme cells. Oncol. Lett. 6, 1435–1438.10.3892/ol.2013.1548Search in Google Scholar
Chawla, A., Boisvert, W.A., Lee, C.H., Laffitte, B.A., Barak, Y., Joseph, S.B., Liao, D., Nagy, L., Edwards, P.A., Curtiss, L.K., et al. (2001). A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol. Cell 7, 161–171.10.1016/S1097-2765(01)00164-2Search in Google Scholar
Choi, Y., Kim, H.S., Shin, K.Y., Kim, E.M., Kim, M., Kim, H.S., Park, C.H., Jeong, Y.H., Yoo, J., Lee, J.P., et al. (2007). Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer’s disease models. Neuropsychopharmacology 32, 2393–2404.10.1038/sj.npp.1301377Search in Google Scholar
Choi, J.H., Choi, A.Y., Yoon, H., Choe, W., Yoon, K.S., Ha, J., Yeo, E.J., and Kang, I. (2010). Baicalein protects HT22 murine hippocampal neuronal cells against endoplasmic reticulum stress-induced apoptosis through inhibition of reactive oxygen species production and CHOP induction. Exp. Mol. Med. 42, 811–822.10.3858/emm.2010.42.12.084Search in Google Scholar
Claessen, B.E., Henriques, J.P., and Dangas, G.D. (2010). Clinical studies with sirolimus, zotarolimus, everolimus, and biolimus A9 drug-eluting stent systems. Curr. Pharm. Des. 16, 4012–4024.10.2174/138161210794454941Search in Google Scholar
Cleary, M.L., Smith, S.D., and Sklar, J. (1986). Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell 47, 19–28.10.1016/0092-8674(86)90362-4Search in Google Scholar
Craig, L.A., Hong, N.S., and McDonald, R.J. (2011). Revisiting the cholinergic hypothesis in the development of Alzheimer’s disease. Neurosci. Biobehav. Rev. 35, 1397–1409.10.1016/j.neubiorev.2011.03.001Search in Google Scholar
Cramer, P.E., Cirrito, J.R., Wesson, D.W., Lee, C.Y., Karlo, J.C., Zinn, A.E., Casali, B.T., Restivo, J.L., Goebel, W.D., James, M.J., et al. (2012). ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science 335, 1503–1506.10.1126/science.1217697Search in Google Scholar
Cruz, J.C., Tseng, H.C., Goldman, J.A., Shih, H., and Tsai, L.H. (2003). Aberrant CDK5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron 40, 471–483.10.1016/S0896-6273(03)00627-5Search in Google Scholar
Cummings, J.L., Morstorf, T., and Zhong, K. (2014). Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res. Ther. 6, 37.10.1186/alzrt269Search in Google Scholar PubMed PubMed Central
da Silva, A.L., Piato, A.L., Bardini, S., Netto, C.A., Nunes, D.S., and Elisabetsky, E. (2004). Memory retrieval improvement by Ptychopetalum olacoides in young and aging mice. J. Ethnopharmacol. 95, 199–203.10.1016/j.jep.2004.07.019Search in Google Scholar PubMed
da Silva, A.L., Piato, A.L., Ferreira, J.G., Martins, B.S., Nunes, D.S., and Elisabetsky, E. (2007). Promnesic effects of Ptychopetalum olacoides in aversive and non-aversive learning paradigms. J. Ethnopharmacol. 109, 449–457.10.1016/j.jep.2006.08.022Search in Google Scholar PubMed
da Silva, A.L., Ferreira, J.G., da Silva Martins, B., Oliveira, S., Mai, N., Nunes, D.S., and Elisabetsky, E. (2008). Serotonin receptors contribute to the promnesic effects of P. olacoides (Marapuama). Physiol. Behav. 95, 88–92.10.1016/j.physbeh.2008.04.022Search in Google Scholar PubMed
da Silva, A.L., Silva Martins, B., Linck Vde, M., Herrmann, A.P., Mai, N., Nunes, D.S., and Elisabetsky, E. (2009). MK801- and scopolamine-induced amnesias are reversed by an Amazonian herbal locally used as a ‘brain tonic’. Psychopharmacology 202, 165–172.10.1007/s00213-008-1272-ySearch in Google Scholar PubMed
Dancey, J.E. and Monzon, J. (2011). Ridaforolimus: a promising drug in the treatment of soft-tissue sarcoma and other malignancies. Fut. Oncol. 7, 827–839.10.2217/fon.11.57Search in Google Scholar PubMed
Daviglus, M.L., Bell, C.C., Berrettini, W., Bowen, P.E., Connolly, E.S., Jr., Cox, N.J., Dunbar-Jacob, J.M., Granieri, E.C., Hunt, G., McGarry, K., et al. (2010). National Institutes of Health State-of-the-Science Conference statement: preventing Alzheimer disease and cognitive decline. Ann. Intern. Med. 153, 176–181.10.7326/0003-4819-153-3-201008030-00260Search in Google Scholar PubMed
Dean, D.C., 3rd, Jerskey, B.A., Chen, K., Protas, H., Thiyyagura, P., Roontiva, A., O’Muircheartaigh, J., Dirks, H., Waskiewicz, N., Lehman, K., et al. (2014). Brain differences in infants at differential genetic risk for late-onset Alzheimer disease: a cross-sectional imaging study. J. Am. Med. Assoc. Neurol. 71, 11–22.10.1001/jamaneurol.2013.4544Search in Google Scholar PubMed PubMed Central
Deiana, S., Harrington, C.R., Wischik, C.M., and Riedel, G. (2009). Methylthioninium chloride reverses cognitive deficits induced by scopolamine: comparison with rivastigmine. Psychopharmacology 202, 53–65.10.1007/s00213-008-1394-2Search in Google Scholar PubMed
Di Pietro, O., Perez-Areales, F.J., Juarez-Jimenez, J., Espargaro, A., Clos, M.V., Perez, B., Lavilla, R., Sabate, R., Luque, F.J., and Munoz-Torrero, D. (2014). Tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrids as a new family of anti-Alzheimer agents targeting beta-amyloid, tau, and cholinesterase pathologies. Eur. J. Med. Chem. 84C, 107–117.10.1016/j.ejmech.2014.07.021Search in Google Scholar PubMed
Dong, G.X. and Feng, Y.P. (2002). Effects of NBP on ATPase and anti-oxidant enzymes activities and lipid peroxidation in transient focal cerebral ischemic rats. Zhongguo yi xue ke xue yuan xue bao. Acta Acad. Med. Sin. 24, 93–97.Search in Google Scholar
Donkin, J.J., Stukas, S., Hirsch-Reinshagen, V., Namjoshi, D., Wilkinson, A., May, S., Chan, J., Fan, J., Collins, J., and Wellington, C.L. (2010). ATP-binding cassette transporter A1 mediates the beneficial effects of the liver X receptor agonist GW3965 on object recognition memory and amyloid burden in amyloid precursor protein/presenilin 1 mice. J. Biol. Chem. 285, 34144–34154.10.1074/jbc.M110.108100Search in Google Scholar
Doody, R.S., Gavrilova, S.I., Sano, M., Thomas, R.G., Aisen, P.S., Bachurin, S.O., Seely, L., and Hung, D.; Dimebon Investigators (2008). Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer’s disease: a randomised, double-blind, placebo-controlled study. Lancet 372, 207–215.10.1016/S0140-6736(08)61074-0Search in Google Scholar
Doody, R.S., Raman, R., Farlow, M., Iwatsubo, T., Vellas, B., Joffe, S., Kieburtz, K., He, F., Sun, X., Thomas, R.G., et al. (2013). A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N. Engl. J. Med. 369, 341–350.10.1056/NEJMoa1210951Search in Google Scholar PubMed
Drechsel, D.N., Hyman, A.A., Cobb, M.H., and Kirschner, M.W. (1992). Modulation of the dynamic instability of tubulin assembly by the microtubule-associated protein tau. Mol. Biol. Cell 3, 1141–1154.10.1091/mbc.3.10.1141Search in Google Scholar PubMed PubMed Central
Eckert, G.P., Renner, K., Eckert, S.H., Eckmann, J., Hagl, S., Abdel-Kader, R.M., Kurz, C., Leuner, K., and Muller, W.E. (2012). Mitochondrial dysfunction – a pharmacological target in Alzheimer’s disease. Mol. Neurobiol. 46, 136–150.10.1007/s12035-012-8271-zSearch in Google Scholar PubMed
Ellgaard, L., Molinari, M., and Helenius, A. (1999). Setting the standards: quality control in the secretory pathway. Science 286, 1882–1888.10.1126/science.286.5446.1882Search in Google Scholar PubMed
Fahrenholz, F. (2007). Alpha-secretase as a therapeutic target. Curr. Alzheimer Res. 4, 412–417.10.2174/156720507781788837Search in Google Scholar PubMed
Fan, L.Y. and Chiu, M.J. (2014). Combotherapy and current concepts as well as future strategies for the treatment of Alzheimer’s disease. Neuropsychiatr. Dis. Treat. 10, 439–451.Search in Google Scholar
Fernandez-Bachiller, M.I., Perez, C., Monjas, L., Rademann, J., and Rodriguez-Franco, M.I. (2012). New tacrine-4-oxo-4H-chromene hybrids as multifunctional agents for the treatment of Alzheimer’s disease, with cholinergic, antioxidant, and beta-amyloid-reducing properties. J. Med. Chem. 55, 1303–1317.10.1021/jm201460ySearch in Google Scholar PubMed
Figueiro, M., Ilha, J., Pochmann, D., Porciuncula, L.O., Xavier, L.L., Achaval, M., Nunes, D.S., and Elisabetsky, E. (2010). Acetylcholinesterase inhibition in cognition-relevant brain areas of mice treated with a nootropic Amazonian herbal (Marapuama). Phytomedicine 17, 956–962.10.1016/j.phymed.2010.03.009Search in Google Scholar PubMed
Figueiro, M., Ilha, J., Linck, V.M., Herrmann, A.P., Nardin, P., Menezes, C.B., Achaval, M., Goncalves, C.A., Porciuncula, L.O., Nunes, D.S., et al. (2011). The Amazonian herbal Marapuama attenuates cognitive impairment and neuroglial degeneration in a mouse Alzheimer model. Phytomedicine 18, 327–333.10.1016/j.phymed.2010.07.013Search in Google Scholar PubMed
Forman, M., Tseng, J., Palcza, J., Leempoels, J., Ramael, S., Krishna, G., Ma, L., Wagner, J., and Troyer, M. (2012). The novel BACE inhibitor MK-8931 dramatically lowers CSF A beta peptides in healthy subjects: results from a rising single dose study. Neurology 78.10.1212/WNL.78.1_MeetingAbstracts.PL02.004Search in Google Scholar
Frisoni, G.B., Bocchetta, M., Chetelat, G., Rabinovici, G.D., de Leon, M.J., Kaye, J., Reiman, E.M., Scheltens, P., Barkhof, F., Black, S.E., et al. (2013). Imaging markers for Alzheimer disease: which vs how. Neurology 81, 487–500.10.1212/WNL.0b013e31829d86e8Search in Google Scholar PubMed PubMed Central
Fu, H., Dou, J., Li, W., Cui, W., Mak, S., Hu, Q., Luo, J., Lam, C.S., Pang, Y., Youdim, M.B., et al. (2009). Promising multifunctional anti-Alzheimer’s dimer bis(7)-cognitin acting as an activator of protein kinase C regulates activities of alpha-secretase and BACE-1 concurrently. Eur. J. Pharmacol. 623, 14–21.10.1016/j.ejphar.2009.09.013Search in Google Scholar PubMed
Goedert, M. and Spillantini, M.G. (2006). A century of Alzheimer’s disease. Science 314, 777–781.10.1126/science.1132814Search in Google Scholar PubMed
Gouras, G.K., Tampellini, D., Takahashi, R.H., and Capetillo-Zarate, E. (2010). Intraneuronal beta-amyloid accumulation and synapse pathology in Alzheimer’s disease. Acta Neuropathol. 119, 523–541.10.1007/s00401-010-0679-9Search in Google Scholar PubMed PubMed Central
Guan, Z.Z. (2008). Cross-talk between oxidative stress and modifications of cholinergic and glutaminergic receptors in the pathogenesis of Alzheimer’s disease. Acta Pharmacol. Sin. 29, 773–780.10.1111/j.1745-7254.2008.00819.xSearch in Google Scholar PubMed
Hardy, J. (2006). A hundred years of Alzheimer’s disease research. Neuron 52, 3–13.10.1016/j.neuron.2006.09.016Search in Google Scholar PubMed
Harman, D. (1956). Aging: a theory based on free radical and radiation chemistry. J. Gerontol. 11, 298–300.10.1093/geronj/11.3.298Search in Google Scholar PubMed
Harrison, D.E., Strong, R., Sharp, Z.D., Nelson, J.F., Astle, C.M., Flurkey, K., Nadon, N.L., Wilkinson, J.E., Frenkel, K., Carter, C.S., et al. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395.10.1038/nature08221Search in Google Scholar PubMed PubMed Central
Heo, H., Shin, Y., Cho, W., Choi, Y., Kim, H., and Kwon, Y.K. (2009). Memory improvement in ibotenic acid induced model rats by extracts of Scutellaria baicalensis. J. Ethnopharmacol. 122, 20–27.10.1016/j.jep.2008.11.026Search in Google Scholar PubMed
Hochfeld, W.E., Lee, S., and Rubinsztein, D.C. (2013). Therapeutic induction of autophagy to modulate neurodegenerative disease progression. Acta Pharmacol. Sin. 34, 600–604.10.1038/aps.2012.189Search in Google Scholar
Hoi, C.P., Ho, Y.P., Baum, L., and Chow, A.H. (2010). Neuroprotective effect of honokiol and magnolol, compounds from Magnolia officinalis, on beta-amyloid-induced toxicity in PC12 cells. Phytother. Res. 24, 1538–1542.10.1002/ptr.3178Search in Google Scholar
Holtzman, D.M. (2001). Role of apoE/Abeta interactions in the pathogenesis of Alzheimer’s disease and cerebral amyloid angiopathy. J. Mol. Neurosci. 17, 147–155.10.1385/JMN:17:2:147Search in Google Scholar
Hoozemans, J.J., van Haastert, E.S., Nijholt, D.A., Rozemuller, A.J., Eikelenboom, P., and Scheper, W. (2009). The unfolded protein response is activated in pretangle neurons in Alzheimer’s disease hippocampus. Am. J. Pathol. 174, 1241–1251.10.2353/ajpath.2009.080814Search in Google Scholar PubMed PubMed Central
Hoshino, T., Nakaya, T., Araki, W., Suzuki, K., Suzuki, T., and Mizushima, T. (2007). Endoplasmic reticulum chaperones inhibit the production of amyloid-beta peptides. Biochem. J. 402, 581–589.10.1042/BJ20061318Search in Google Scholar PubMed PubMed Central
Huang, Y. and Mucke, L. (2012). Alzheimer mechanisms and therapeutic strategies. Cell 148, 1204–1222.10.1016/j.cell.2012.02.040Search in Google Scholar PubMed PubMed Central
Hung, S.Y., Huang, W.P., Liou, H.C., and Fu, W.M. (2009). Autophagy protects neuron from Abeta-induced cytotoxicity. Autophagy 5, 502–510.10.4161/auto.5.4.8096Search in Google Scholar PubMed
Hyman, B.T. (2011). Amyloid-dependent and amyloid-independent stages of Alzheimer disease. Arch. Neurol. 68, 1062–1064.10.1001/archneurol.2011.70Search in Google Scholar PubMed
Iqbal, K., Alonso Adel, C., Chen, S., Chohan, M.O., El-Akkad, E., Gong, C.X., Khatoon, S., Li, B., Liu, F., Rahman, A., et al. (2005). Tau pathology in Alzheimer disease and other tauopathies. Biochim. Biophys. Acta 1739, 198–210.10.1016/j.bbadis.2004.09.008Search in Google Scholar PubMed
James, B.D., Leurgans, S.E., Hebert, L.E., Scherr, P.A., Yaffe, K., and Bennett, D.A. (2014). Contribution of Alzheimer disease to mortality in the United States. Neurology 82, 1045–1050.10.1212/WNL.0000000000000240Search in Google Scholar PubMed PubMed Central
Jayaraman, A., Carroll, J.C., Morgan, T.E., Lin, S., Zhao, L., Arimoto, J.M., Murphy, M.P., Beckett, T.L., Finch, C.E., Brinton, R.D., et al. (2012). 17Beta-estradiol and progesterone regulate expression of beta-amyloid clearance factors in primary neuron cultures and female rat brain. Endocrinology 153, 5467–5479.10.1210/en.2012-1464Search in Google Scholar PubMed PubMed Central
Jiang, Q., Lee, C.Y., Mandrekar, S., Wilkinson, B., Cramer, P., Zelcer, N., Mann, K., Lamb, B., Willson, T.M., Collins, J.L., et al. (2008). ApoE promotes the proteolytic degradation of Abeta. Neuron 58, 681–693.10.1016/j.neuron.2008.04.010Search in Google Scholar PubMed PubMed Central
Johnson, S.C., Rabinovitch, P.S., and Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. Nature 493, 338–345.10.1038/nature11861Search in Google Scholar PubMed PubMed Central
Jung, C.G., Horike, H., Cha, B.Y., Uhm, K.O., Yamauchi, R., Yamaguchi, T., Hosono, T., Iida, K., Woo, J.T., and Michikawa, M. (2010a). Honokiol increases ABCA1 expression level by activating retinoid X receptor beta. Biol. Pharm. Bull. 33, 1105–1111.10.1248/bpb.33.1105Search in Google Scholar PubMed
Jung, C.H., Ro, S.H., Cao, J., Otto, N.M., and Kim, D.H. (2010b). mTOR regulation of autophagy. FEBS Lett. 584, 1287–1295.10.1016/j.febslet.2010.01.017Search in Google Scholar PubMed PubMed Central
Kanekiyo, T., Xu, H., and Bu, G. (2014). ApoE and Abeta in Alzheimer’s disease: accidental encounters or partners? Neuron 81, 740–754.10.1016/j.neuron.2014.01.045Search in Google Scholar PubMed PubMed Central
Kaufman, R.J. (2002). Orchestrating the unfolded protein response in health and disease. J. Clin. Invest. 110, 1389–1398.10.1172/JCI0216886Search in Google Scholar
Kaushik, G., Ramalingam, S., Subramaniam, D., Rangarajan, P., Protti, P., Rammamoorthy, P., Anant, S., and Mammen, J.M. (2012). Honokiol induces cytotoxic and cytostatic effects in malignant melanoma cancer cells. Am. J. Surg. 204, 868–873.10.1016/j.amjsurg.2012.09.001Search in Google Scholar PubMed PubMed Central
Kawas, C., Resnick, S., Morrison, A., Brookmeyer, R., Corrada, M., Zonderman, A., Bacal, C., Lingle, D.D., and Metter, E. (1997). A prospective study of estrogen replacement therapy and the risk of developing Alzheimer’s disease: the Baltimore Longitudinal Study of Aging. Neurology 48, 1517–1521.10.1212/WNL.48.6.1517Search in Google Scholar PubMed
Kim, J., Kundu, M., Viollet, B., and Guan, K.L. (2011). AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13, 132–141.10.1038/ncb2152Search in Google Scholar PubMed PubMed Central
Kircik, L.H. (2010). Doxycycline and minocycline for the management of acne: a review of efficacy and safety with emphasis on clinical implications. J. Drugs. Dermatol. 9, 1407–1411.Search in Google Scholar
Kotani, H., Tanabe, H., Mizukami, H., Amagaya, S., and Inoue, M. (2012). A naturally occurring rexinoid, honokiol, can serve as a regulator of various retinoid X receptor heterodimers. Biol. Pharm. Bull. 35, 1–9.10.1248/bpb.35.1Search in Google Scholar
LaDu, M.J., Pederson, T.M., Frail, D.E., Reardon, C.A., Getz, G.S., and Falduto, M.T. (1995). Purification of apolipoprotein E attenuates isoform-specific binding to beta-amyloid. J. Biol. Chem. 270, 9039–9042.10.1074/jbc.270.16.9039Search in Google Scholar
Lafay-Chebassier, C., Paccalin, M., Page, G., Barc-Pain, S., Perault-Pochat, M.C., Gil, R., Pradier, L., and Hugon, J. (2005). mTOR/p70S6k signalling alteration by Abeta exposure as well as in APP-PS1 transgenic models and in patients with Alzheimer’s disease. J. Neurochem. 94, 215–225.10.1111/j.1471-4159.2005.03187.xSearch in Google Scholar
Landmark, K. and Reikvam, A. (2008). Cholinesterase inhibitors in the treatment of dementia – are they useful in clinical practice? Tidsskr. Nor. Legeforen. 128, 294–297.Search in Google Scholar
Laplante, M. and Sabatini, D.M. (2012). mTOR signaling in growth control and disease. Cell 149, 274–293.10.1016/j.cell.2012.03.017Search in Google Scholar
Leon, R., Garcia, A.G., and Marco-Contelles, J. (2013). Recent advances in the multitarget-directed ligands approach for the treatment of Alzheimer’s disease. Med. Res. Rev. 33, 139–189.10.1002/med.20248Search in Google Scholar
Li, X., Alafuzoff, I., Soininen, H., Winblad, B., and Pei, J.J. (2005). Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer’s disease brain. FEBS J. 272, 4211–4220.10.1111/j.1742-4658.2005.04833.xSearch in Google Scholar
Li, W., Mak, M., Jiang, H., Wang, Q., Pang, Y., Chen, K., and Han, Y. (2009). Novel anti-Alzheimer’s dimer bis(7)-cognitin: cellular and molecular mechanisms of neuroprotection through multiple targets. Neurotherapeutics 6, 187–201.10.1016/j.nurt.2008.10.040Search in Google Scholar
Li, S.Y., Jiang, N., Xie, S.S., Wang, K.D., Wang, X.B., and Kong, L.Y. (2014). Design, synthesis and evaluation of novel tacrine-rhein hybrids as multifunctional agents for the treatment of Alzheimer’s disease. Org. Biomol. Chem. 12, 801–814.10.1039/C3OB42010HSearch in Google Scholar
Lichtenthaler, S.F. (2011). alpha-Secretase in Alzheimer’s disease: molecular identity, regulation and therapeutic potential. J. Neurochem. 116, 10–21.10.1111/j.1471-4159.2010.07081.xSearch in Google Scholar
Linton, S., Davies, M.J., and Dean, R.T. (2001). Protein oxidation and ageing. Exp. Gerontol. 36, 1503–1518.10.1016/S0531-5565(01)00136-XSearch in Google Scholar
Liu, C., Wu, J., Gu, J., Xiong, Z., Wang, F., Wang, J., Wang, W., and Chen, J. (2007). Baicalein improves cognitive deficits induced by chronic cerebral hypoperfusion in rats. Pharmacol. Biochem. Behav. 86, 423–430.10.1016/j.pbb.2006.11.005Search in Google Scholar
Lucas, J.J., Hernandez, F., Gomez-Ramos, P., Moran, M.A., Hen, R., and Avila, J. (2001). Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. EMBO J. 20, 27–39.10.1093/emboj/20.1.27Search in Google Scholar
Ma, T. and Klann, E. (2012). Amyloid beta: linking synaptic plasticity failure to memory disruption in Alzheimer’s disease. J. Neurochem. 120(Suppl 1), 140–148.10.1111/j.1471-4159.2011.07506.xSearch in Google Scholar
Macario, A.J. and Conway de Macario, E. (2002). Sick chaperones and ageing: a perspective. Ageing Res. Rev. 1, 295–311.10.1016/S1568-1637(01)00005-8Search in Google Scholar
Maiese, K., Chong, Z.Z., Wang, S., and Shang, Y.C. (2012). Oxidant stress and signal transduction in the nervous system with the PI 3-K, Akt, and mTOR cascade. Int. J. Mol. Sci. 13, 13830–13866.10.3390/ijms131113830Search in Google Scholar PubMed PubMed Central
Majumder, S., Caccamo, A., Medina, D.X., Benavides, A.D., Javors, M.A., Kraig, E., Strong, R., Richardson, A., and Oddo, S. (2012). Lifelong rapamycin administration ameliorates age-dependent cognitive deficits by reducing IL-1beta and enhancing NMDA signaling. Aging Cell 11, 326–335.10.1111/j.1474-9726.2011.00791.xSearch in Google Scholar PubMed PubMed Central
Marcade, M., Bourdin, J., Loiseau, N., Peillon, H., Rayer, A., Drouin, D., Schweighoffer, F., and Desire, L. (2008). Etazolate, a neuroprotective drug linking GABA(A) receptor pharmacology to amyloid precursor protein processing. J. Neurochem. 106, 392–404.10.1111/j.1471-4159.2008.05396.xSearch in Google Scholar PubMed
Martenyi, F., Willis, B., Dean, R., Gonzales, C., Komjathy, S., Monk, S., Lowe, S., Daugherty, L., Nakano, M., Mergott, D., et al. (2013). Pharmacokinetic (PK) and pharmacodynamic (PD) effects of BACE inhibitor LY2886721 in healthy volunteers (HVs) at steady state. Neurology 80.Search in Google Scholar
Martone, R.L., Zhou, H., Atchison, K., Comery, T., Xu, J.Z., Huang, X., Gong, X., Jin, M., Kreft, A., Harrison, B., et al. (2009). Begacestat (GSI-953): a novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein gamma-secretase for the treatment of Alzheimer’s disease. J. Pharmacol. Exp. Ther. 331, 598–608.10.1124/jpet.109.152975Search in Google Scholar PubMed
Matrone, C., Djelloul, M., Taglialatela, G., and Perrone, L. (2014). Inflammatory risk factors and pathologies promoting Alzheimer’s disease progression: is RAGE the key? Histol. Histopathol.Search in Google Scholar
Mazzitelli, S., Xu, P., Ferrer, I., Davis, R.J., and Tournier, C. (2011). The loss of c-Jun N-terminal protein kinase activity prevents the amyloidogenic cleavage of amyloid precursor protein and the formation of amyloid plaques in vivo. J. Neurosci. 31, 16969–16976.10.1523/JNEUROSCI.4491-11.2011Search in Google Scholar PubMed PubMed Central
McCormick, M.A., Tsai, S.Y., and Kennedy, B.K. (2011). TOR and ageing: a complex pathway for a complex process. Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci. 366, 17–27.Search in Google Scholar
Morikawa, M., Fryer, J.D., Sullivan, P.M., Christopher, E.A., Wahrle, S.E., DeMattos, R.B., O’Dell, M.A., Fagan, A.M., Lashuel, H.A., Walz, T., et al. (2005). Production and characterization of astrocyte-derived human apolipoprotein E isoforms from immortalized astrocytes and their interactions with amyloid-beta. Neurobiol. Dis. 19, 66–76.10.1016/j.nbd.2004.11.005Search in Google Scholar PubMed
Morselli, E., Galluzzi, L., Kepp, O., Criollo, A., Maiuri, M.C., Tavernarakis, N., Madeo, F., and Kroemer, G. (2009). Autophagy mediates pharmacological lifespan extension by spermidine and resveratrol. Aging 1, 961–970.10.18632/aging.100110Search in Google Scholar
Nie, Q., Du, X.G., and Geng, M.Y. (2011). Small molecule inhibitors of amyloid beta peptide aggregation as a potential therapeutic strategy for Alzheimer’s disease. Acta Pharmacol. Sin. 32, 545–551.10.1038/aps.2011.14Search in Google Scholar
Oakley, H., Cole, S.L., Logan, S., Maus, E., Shao, P., Craft, J., Guillozet-Bongaarts, A., Ohno, M., Disterhoft, J., Van Eldik, L., et al. (2006). Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J. Neurosci. 26, 10129–10140.10.1523/JNEUROSCI.1202-06.2006Search in Google Scholar
O’Neill, C. (2013). PI3-kinase/Akt/mTOR signaling: impaired on/off switches in aging, cognitive decline and Alzheimer’s disease. Exp. Gerontol. 48, 647–653.10.1016/j.exger.2013.02.025Search in Google Scholar
Onor, M.L., Trevisiol, M., and Aguglia, E. (2007). Rivastigmine in the treatment of Alzheimer’s disease: an update. Clin. Interv. Aging 2, 17–32.10.2147/ciia.2007.2.1.17Search in Google Scholar
Paccalin, M., Pain-Barc, S., Pluchon, C., Paul, C., Besson, M.N., Carret-Rebillat, A.S., Rioux-Bilan, A., Gil, R., and Hugon, J. (2006). Activated mTOR and PKR kinases in lymphocytes correlate with memory and cognitive decline in Alzheimer’s disease. Dementia Geriatr. Cognit. Disord. 22, 320–326.10.1159/000095562Search in Google Scholar
Panza, F., Frisardi, V., Solfrizzi, V., Imbimbo, B.P., Logroscino, G., Santamato, A., Greco, A., Seripa, D., and Pilotto, A. (2012). Immunotherapy for Alzheimer’s disease: from anti-beta-amyloid to tau-based immunization strategies. Immunotherapy 4, 213–238.10.2217/imt.11.170Search in Google Scholar
Pei, J.J. and Hugon, J. (2008). mTOR-dependent signalling in Alzheimer’s disease. J. Cell. Mol. Med. 12, 2525–2532.10.1111/j.1582-4934.2008.00509.xSearch in Google Scholar
Pei, J.J., Grundke-Iqbal, I., Iqbal, K., Bogdanovic, N., Winblad, B., and Cowburn, R.F. (1998). Accumulation of cyclin-dependent kinase 5 (CDK5) in neurons with early stages of Alzheimer’s disease neurofibrillary degeneration. Brain Res. 797, 267–277.10.1016/S0006-8993(98)00296-0Search in Google Scholar
Peng, Y., Xu, S., Chen, G., Wang, L., Feng, Y., and Wang, X. (2007). L-3-n-butylphthalide improves cognitive impairment induced by chronic cerebral hypoperfusion in rats. J. Pharmacol. Exp. Ther. 321, 902–910.10.1124/jpet.106.118760Search in Google Scholar PubMed
Peng, Y., Xing, C., Xu, S., Lemere, C.A., Chen, G., Liu, B., Wang, L., Feng, Y., and Wang, X. (2009). L-3-n-butylphthalide improves cognitive impairment induced by intracerebroventricular infusion of amyloid-beta peptide in rats. Eur. J. Pharmacol. 621, 38–45.10.1016/j.ejphar.2009.08.036Search in Google Scholar PubMed
Peng, Y., Sun, J., Hon, S., Nylander, A.N., Xia, W., Feng, Y., Wang, X., and Lemere, C.A. (2010). L-3-n-butylphthalide improves cognitive impairment and reduces amyloid-beta in a transgenic model of Alzheimer’s disease. J. Neurosci. 30, 8180–8189.10.1523/JNEUROSCI.0340-10.2010Search in Google Scholar PubMed PubMed Central
Peng, Y., Hu, Y., Xu, S., Rong, X., Li, J., Li, P., Wang, L., Yang, J., and Wang, X. (2014). Potassium 2-(1-hydroxypentyl)-benzoate improves memory deficits and attenuates amyloid and tau pathologies in a mouse model of Alzheimer’s disease. J. Pharmacol. Exp. Ther. 350, 361–374.10.1124/jpet.114.213140Search in Google Scholar PubMed
Pettersson, M., Stepan, A.F., Kauffman, G.W., and Johnson, D.S. (2013). Novel gamma-secretase modulators for the treatment of Alzheimer’s disease: a review focusing on patents from 2010 to 2012. Exp. Opin. Ther. Pat. 23, 1349–1366.10.1517/13543776.2013.821465Search in Google Scholar PubMed
Piato, A.L., Detanico, B.C., Jesus, J.F., Lhullier, F.L., Nunes, D.S., and Elisabetsky, E. (2008). Effects of Marapuama in the chronic mild stress model: further indication of antidepressant properties. J. Ethnopharmacol. 118, 300–304.10.1016/j.jep.2008.04.018Search in Google Scholar PubMed
Pike, C.J. (1999). Estrogen modulates neuronal Bcl-xL expression and beta-amyloid-induced apoptosis: relevance to Alzheimer’s disease. J. Neurochem. 72, 1552–1563.10.1046/j.1471-4159.1999.721552.xSearch in Google Scholar PubMed
Pratico, D. (2008). Oxidative stress hypothesis in Alzheimer’s disease: a reappraisal. Trends Pharmacol. Sci. 29, 609–615.10.1016/j.tips.2008.09.001Search in Google Scholar PubMed
Raina, P., Santaguida, P., Ismaila, A., Patterson, C., Cowan, D., Levine, M., Booker, L., and Oremus, M. (2008). Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann. Intern. Med. 148, 379–397.10.7326/0003-4819-148-5-200803040-00009Search in Google Scholar PubMed
Reddy, P.H. and Reddy, T.P. (2011). Mitochondria as a therapeutic target for aging and neurodegenerative diseases. Curr. Alzheimer Res. 8, 393–409.10.2174/156720511795745401Search in Google Scholar PubMed PubMed Central
Reitz, C. (2012). Alzheimer’s disease and the amyloid cascade hypothesis: a critical review. Int. J. Alzheimers Dis. 2012, 369808.10.1155/2012/369808Search in Google Scholar PubMed PubMed Central
Reitz, C. and Mayeux, R. (2014). Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem. Pharmacol. 88, 640–651.10.1016/j.bcp.2013.12.024Search in Google Scholar
Resende, R., Ferreiro, E., Pereira, C., and Oliveira, C.R. (2008). ER stress is involved in Abeta-induced GSK-3beta activation and tau phosphorylation. J. Neurosci. Res. 86, 2091–2099.10.1002/jnr.21648Search in Google Scholar
Ricobaraza, A., Cuadrado-Tejedor, M., Marco, S., Perez-Otano, I., and Garcia-Osta, A. (2012). Phenylbutyrate rescues dendritic spine loss associated with memory deficits in a mouse model of Alzheimer disease. Hippocampus 22, 1040–1050.10.1002/hipo.20883Search in Google Scholar
Rodriguez-Franco, M.I., Fernandez-Bachiller, M.I., Perez, C., Hernandez-Ledesma, B., and Bartolome, B. (2006). Novel tacrine-melatonin hybrids as dual-acting drugs for Alzheimer disease, with improved acetylcholinesterase inhibitory and antioxidant properties. J. Med. Chem. 49, 459–462.10.1021/jm050746dSearch in Google Scholar
Ryu, J.K., Franciosi, S., Sattayaprasert, P., Kim, S.U., and McLarnon, J.G. (2004). Minocycline inhibits neuronal death and glial activation induced by beta-amyloid peptide in rat hippocampus. Glia 48, 85–90.10.1002/glia.20051Search in Google Scholar
Sastre, J., Pallardo, F.V., and Vina, J. (2003). The role of mitochondrial oxidative stress in aging. Free Radic. Biol. Med. 35, 1–8.10.1016/S0891-5849(03)00184-9Search in Google Scholar
Schellekens, H., McNamara, O., Dinan, T.G., McCarthy, J.V., McGlacken, G.P., and Cryan, J.F. (2013). Semagacestat, a gamma-secretase inhibitor, activates the growth hormone secretagogue (GHS-R1a) receptor. J. Pharm. Pharmacol. 65, 528–538.10.1111/jphp.12010Search in Google Scholar PubMed
Schneider, L.S., Mangialasche, F., Andreasen, N., Feldman, H., Giacobini, E., Jones, R., Mantua, V., Mecocci, P., Pani, L., Winblad, B., et al. (2014). Clinical trials and late-stage drug development for Alzheimer’s disease: an appraisal from 1984 to 2014. J. Intern. Med. 275, 251–283.10.1111/joim.12191Search in Google Scholar PubMed PubMed Central
Seabrook, T.J., Jiang, L., Maier, M., and Lemere, C.A. (2006). Minocycline affects microglia activation, Abeta deposition, and behavior in APP-tg mice. Glia 53, 776–782.10.1002/glia.20338Search in Google Scholar PubMed
Sendur, M.A., Zengin, N., Aksoy, S., and Altundag, K. (2014). Everolimus: a new hope for patients with breast cancer. Curr. Med. Res. Opin. 30, 75–87.10.1185/03007995.2013.846253Search in Google Scholar PubMed
Shao, B.Y., Xia, Z., Xie, Q., Ge, X.X., Zhang, W.W., Sun, J., Jiang, P., Wang, H., Le, W.D., Qiu, Z.B., et al. (2014). Meserine, a novel carbamate AChE inhibitor, ameliorates scopolamine-induced dementia and alleviates amyloidogenesis of APP/PS1 transgenic mice. CNS Neurosci. Ther. 20, 165–171.10.1111/cns.12183Search in Google Scholar
Simons, M., de Strooper, B., Multhaup, G., Tienari, P.J., Dotti, C.G., and Beyreuther, K. (1996). Amyloidogenic processing of the human amyloid precursor protein in primary cultures of rat hippocampal neurons. J. Neurosci. 16, 899–908.10.1523/JNEUROSCI.16-03-00899.1996Search in Google Scholar
Siqueira, I.R., Fochesatto, C., da Silva, A.L., Nunes, D.S., Battastini, A.M., Netto, C.A., and Elisabetsky, E. (2003). Ptychopetalum olacoides, a traditional Amazonian ‘nerve tonic’, possesses anticholinesterase activity. Pharmacol. Biochem. Behav. 75, 645–650.10.1016/S0091-3057(03)00113-8Search in Google Scholar
Siqueira, I.R., Cimarosti, H., Fochesatto, C., Nunes, D.S., Salbego, C., Elisabetsky, E., and Netto, C.A. (2004). Neuroprotective effects of Ptychopetalum olacoides Bentham (Olacaceae) on oxygen and glucose deprivation induced damage in rat hippocampal slices. Life Sci. 75, 1897–1906.10.1016/j.lfs.2004.06.001Search in Google Scholar PubMed
Snow, A.D., Cummings, J., Lake, T., Hu, Q., Esposito, L., Cam, J., Hudson, M., Smith, E., and Runnels, S. (2009). Exebryl-1: a novel small molecule currently in human clinical trials as a disease-modifying drug for the treatment of Alzheimer’s disease. Alzheimers Dementia 5, P418.10.1016/j.jalz.2009.04.925Search in Google Scholar
Steele, J.W. and Gandy, S. (2013). Latrepirdine (Dimebon(R)), a potential Alzheimer therapeutic, regulates autophagy and neuropathology in an Alzheimer mouse model. Autophagy 9, 617–618.10.4161/auto.23487Search in Google Scholar PubMed PubMed Central
Stenner-Liewen, F., Grunwald, V., Greil, R., and Porta, C. (2013). The clinical potential of temsirolimus in second or later lines of treatment for metastatic renal cell carcinoma. Exp. Rev. Anticancer Ther. 13, 1021–1033.10.1586/14737140.2013.833684Search in Google Scholar PubMed
Swerdlow, R.H. (2012). Alzheimer’s disease pathologic cascades: who comes first, what drives what. Neurotox. Res. 22, 182–194.10.1007/s12640-011-9272-9Search in Google Scholar PubMed PubMed Central
Thies, W. and Bleiler, L., Alzheimer’s Association (2013). 2013 Alzheimer’s disease facts and figures. Alzheimers Dementia 9, 208–245.Search in Google Scholar
Tiraboschi, P., Hansen, L.A., Thal, L.J., and Corey-Bloom, J. (2004). The importance of neuritic plaques and tangles to the development and evolution of AD. Neurology 62, 1984–1989.10.1212/01.WNL.0000129697.01779.0ASearch in Google Scholar PubMed
Tokuda, T., Calero, M., Matsubara, E., Vidal, R., Kumar, A., Permanne, B., Zlokovic, B., Smith, J.D., LaDu, M.J., Rostagno, A., et al. (2000). Lipidation of apolipoprotein E influences its isoform-specific interaction with Alzheimer’s amyloid beta peptides. Biochem. J. 348 Pt 2, 359–365.10.1042/bj3480359Search in Google Scholar
Tomita, T. and Iwatsubo, T. (2013). Structural biology of presenilins and signal peptide peptidases. J. Biol. Chem. 288, 14673–14680.10.1074/jbc.R113.463281Search in Google Scholar PubMed PubMed Central
Trepanier, C.H. and Milgram, N.W. (2010). Neuroinflammation in Alzheimer’s disease: are NSAIDs and selective COX-2 inhibitors the next line of therapy? J. Alzheimers Dis. 21, 1089–1099.10.3233/JAD-2010-090667Search in Google Scholar
Tumiatti, V., Minarini, A., Bolognesi, M.L., Milelli, A., Rosini, M., and Melchiorre, C. (2010). Tacrine derivatives and Alzheimer’s disease. Curr. Med. Chem. 17, 1825–1838.10.2174/092986710791111206Search in Google Scholar PubMed
Viayna, E., Sola, I., Bartolini, M., De Simone, A., Tapia-Rojas, C., Serrano, F.G., Sabate, R., Juarez-Jimenez, J., Perez, B., Luque, F.J., et al. (2014). Synthesis and multitarget biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents. J. Med. Chem. 57, 2549–2567.10.1021/jm401824wSearch in Google Scholar PubMed
Vignini, A., Giulietti, A., Nanetti, L., Raffaelli, F., Giusti, L., Mazzanti, L., and Provinciali, L. (2013). Alzheimer’s disease and diabetes: new insights and unifying therapies. Curr. Diabetes Rev. 9, 218–227.10.2174/1573399811309030003Search in Google Scholar PubMed
Vincent, B. and Govitrapong, P. (2011). Activation of the alpha-secretase processing of AbetaPP as a therapeutic approach in Alzheimer’s disease. J. Alzheimers Dis. 24(Suppl 2), 75–94.10.3233/JAD-2011-110218Search in Google Scholar PubMed
Walsh, D.M. and Selkoe, D.J. (2004). Deciphering the molecular basis of memory failure in Alzheimer’s disease. Neuron 44, 181–193.10.1016/j.neuron.2004.09.010Search in Google Scholar PubMed
Wang, S.Y., Wang, H.H., Chi, C.W., Chen, C.F., and Liao, J.F. (2004). Effects of baicalein on beta-amyloid peptide-(25-35)-induced amnesia in mice. Eur. J. Pharmacol. 506, 55–61.10.1016/j.ejphar.2004.10.029Search in Google Scholar PubMed
Wang, X., Su, B., Lee, H.G., Li, X., Perry, G., Smith, M.A., and Zhu, X. (2009). Impaired balance of mitochondrial fission and fusion in Alzheimer’s disease. J. Neurosci. 29, 9090–9103.10.1523/JNEUROSCI.1357-09.2009Search in Google Scholar PubMed PubMed Central
Wang, C., Yu, J.T., Miao, D., Wu, Z.C., Tan, M.S., and Tan, L. (2014). Targeting the mTOR signaling network for Alzheimer’s disease therapy. Mol. Neurobiol. 49, 120–135.10.1007/s12035-013-8505-8Search in Google Scholar PubMed
Watkins, P.B., Zimmerman, H.J., Knapp, M.J., Gracon, S.I., and Lewis, K.W. (1994). Hepatotoxic effects of tacrine administration in patients with Alzheimer’s disease. J. Am. Med. Assoc. 271, 992–998.10.1001/jama.1994.03510370044030Search in Google Scholar
Wen, Y., Planel, E., Herman, M., Figueroa, H.Y., Wang, L., Liu, L., Lau, L.F., Yu, W.H., and Duff, K.E. (2008). Interplay between cyclin-dependent kinase 5 and glycogen synthase kinase 3 beta mediated by neuregulin signaling leads to differential effects on tau phosphorylation and amyloid precursor protein processing. J. Neurosci. 28, 2624–2632.10.1523/JNEUROSCI.5245-07.2008Search in Google Scholar
Weuve, J., Hebert, L.E., Scherr, P.A., and Evans, D.A. (2014). Deaths in the United States among persons with Alzheimer’s disease (2010–2050). Alzheimers Dementia 10, e40–e46.10.1016/j.jalz.2014.01.004Search in Google Scholar
Wu, T.W., Wang, J.M., Chen, S., and Brinton, R.D. (2005). 17Beta-estradiol induced Ca2+ influx via L-type calcium channels activates the Src/ERK/cyclic-AMP response element binding protein signal pathway and BCL-2 expression in rat hippocampal neurons: a potential initiation mechanism for estrogen-induced neuroprotection. Neuroscience 135, 59–72.10.1016/j.neuroscience.2004.12.027Search in Google Scholar
Xie, S.S., Wang, X.B., Li, J.Y., Yang, L., and Kong, L.Y. (2013). Design, synthesis and evaluation of novel tacrine-coumarin hybrids as multifunctional cholinesterase inhibitors against Alzheimer’s disease. Eur. J. Med. Chem. 64, 540–553.10.1016/j.ejmech.2013.03.051Search in Google Scholar
Xu, Q., Li, Y., Cyras, C., Sanan, D.A., and Cordell, B. (2000). Isolation and characterization of apolipoproteins from murine microglia. Identification of a low density lipoprotein-like apolipoprotein J-rich but E-poor spherical particle. J. Biol. Chem. 275, 31770–31777.10.1074/jbc.M002796200Search in Google Scholar
Xu, Q., Bernardo, A., Walker, D., Kanegawa, T., Mahley, R.W., and Huang, Y. (2006). Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus. J. Neurosci. 26, 4985–4994.10.1523/JNEUROSCI.5476-05.2006Search in Google Scholar
Yan, R. and Vassar, R. (2014). Targeting the beta secretase BACE1 for Alzheimer’s disease therapy. Lancet Neurol. 13, 319–329.10.1016/S1474-4422(13)70276-XSearch in Google Scholar
Yan, S.D., Yan, S.F., Chen, X., Fu, J., Chen, M., Kuppusamy, P., Smith, M.A., Perry, G., Godman, G.C., Nawroth, P., et al. (1995). Non-enzymatically glycated tau in Alzheimer’s disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid beta-peptide. Nat. Med. 1, 693–699.10.1038/nm0795-693Search in Google Scholar PubMed
Yang, Y., Turner, R.S., and Gaut, J.R. (1998). The chaperone BiP/GRP78 binds to amyloid precursor protein and decreases Abeta40 and Abeta42 secretion. J. Biol. Chem. 273, 25552–25555.10.1074/jbc.273.40.25552Search in Google Scholar PubMed
Yao, M., Nguyen, T.V., and Pike, C.J. (2005). Beta-amyloid-induced neuronal apoptosis involves c-Jun N-terminal kinase-dependent downregulation of Bcl-w. J. Neurosci. 25, 1149–1158.10.1523/JNEUROSCI.4736-04.2005Search in Google Scholar PubMed PubMed Central
Yoon, S.S. and Jo, S.A. (2012). Mechanisms of amyloid-beta peptide clearance: potential therapeutic targets for Alzheimer’s disease. Biomol. Ther. 20, 245–255.10.4062/biomolther.2012.20.3.245Search in Google Scholar PubMed PubMed Central
Yoon, S.O., Park, D.J., Ryu, J.C., Ozer, H.G., Tep, C., Shin, Y.J., Lim, T.H., Pastorino, L., Kunwar, A.J., Walton, J.C., et al. (2012). JNK3 perpetuates metabolic stress induced by Abeta peptides. Neuron 75, 824–837.10.1016/j.neuron.2012.06.024Search in Google Scholar PubMed PubMed Central
Yuan, J., Venkatraman, S., Zheng, Y., McKeever, B.M., Dillard, L.W., and Singh, S.B. (2013). Structure-based design of beta-site APP cleaving enzyme 1 (BACE1) inhibitors for the treatment of Alzheimer’s disease. J. Med. Chem. 56, 4156–4180.10.1021/jm301659nSearch in Google Scholar PubMed
Zandi, P.P., Carlson, M.C., Plassman, B.L., Welsh-Bohmer, K.A., Mayer, L.S., Steffens, D.C., and Breitner, J.C.; Cache County Memory Study I (2002). Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study. J. Am. Med. Assoc. 288, 2123–2129.10.1001/jama.288.17.2123Search in Google Scholar PubMed
Zhang, Y., Wang, L., Li, J., and Wang, X.L. (2006). 2-(1-Hydroxypentyl)-benzoate increases cerebral blood flow and reduces infarct volume in rats model of transient focal cerebral ischemia. J. Pharmacol. Exp. Ther. 317, 973–979.10.1124/jpet.105.098517Search in Google Scholar PubMed
Zhang, S., Hedskog, L., Petersen, C.A., Winblad, B., and Ankarcrona, M. (2010). Dimebon (latrepirdine) enhances mitochondrial function and protects neuronal cells from death. J. Alzheimers Dis. 21, 389–402.10.3233/JAD-2010-100174Search in Google Scholar PubMed
Zhang, S.Q., Obregon, D., Ehrhart, J., Deng, J., Tian, J., Hou, H., Giunta, B., Sawmiller, D., and Tan, J. (2013). Baicalein reduces beta-amyloid and promotes nonamyloidogenic amyloid precursor protein processing in an Alzheimer’s disease transgenic mouse model. J. Neurosci. Res. 91, 1239–1246.10.1002/jnr.23244Search in Google Scholar PubMed PubMed Central
Zhu, S., Stavrovskaya, I.G., Drozda, M., Kim, B.Y., Ona, V., Li, M., Sarang, S., Liu, A.S., Hartley, D.M., Wu, D.C., et al. (2002). Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature 417, 74–78.10.1038/417074aSearch in Google Scholar PubMed
Zhu, Z., Li, C., Wang, X., Yang, Z., Chen, J., Hu, L., Jiang, H., and Shen, X. (2010). 2,2′,4′-trihydroxychalcone from Glycyrrhiza glabra as a new specific BACE1 inhibitor efficiently ameliorates memory impairment in mice. J. Neurochem. 114, 374–385.10.1111/j.1471-4159.2010.06751.xSearch in Google Scholar PubMed
Zhu, Z., Yan, J., Jiang, W., Yao, X.G., Chen, J., Chen, L., Li, C., Hu, L., Jiang, H., and Shen, X. (2013). Arctigenin effectively ameliorates memory impairment in Alzheimer’s disease model mice targeting both beta-amyloid production and clearance. J. Neurosci. 33, 13138–13149.10.1523/JNEUROSCI.4790-12.2013Search in Google Scholar PubMed PubMed Central
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