AAD  Vol.3 No.3 , September 2014
Strategizing the Development of Alzheimer’s Therapeutics
ABSTRACT
Alzheimer’s Disease is a complex, progressive condition with symptoms that do not reveal themselves until significant changes to neuronal morphology have already occurred. The delayed manifestation of cognitive decline makes determination of the true etiological origins difficult. As a result, identification of ideal drug targets becomes seemingly impossible. The existing treatments for Alzheimer’s Disease may temporarily suppress the rate of cognitive decline, but do little to slow or halt neuronal decay. While many believe that the current approaches to identifying a cure for the disease are too narrow-minded, focusing heavily on the physical manifestations of the diseased brain such as amyloid plaques and neurofibrillary tangles, this review asserts the status of Alzheimer’s research as rational and multi-faceted.

Cite this paper
Davis, J. and Couch, R. (2014) Strategizing the Development of Alzheimer’s Therapeutics. Advances in Alzheimer's Disease, 3, 107-127. doi: 10.4236/aad.2014.33011.
References
[1]   World Health Organization and Alzheimer’s Disease International (2012) Dementia: A Public Health Priority. World Health Organization, Geneva, London.

[2]   Corbett, A., et al. (2012) Drug Repositioning for Alzheimer’s Disease. Nature Reviews Drug Discovery, 11, 833-846. http://dx.doi.org/10.1038/nrd3869

[3]   Alzheimer’s Association (2014) Alzheimer’s Disease Facts and Figures. Alzheimer’s and Dementia, 10, e47-e92. http://dx.doi.org/10.1016/j.jalz.2014.02.001

[4]   Lopez, O.L. (2011) The Growing Burden of Alzheimer’s Disease. The American Journal of Managed Care, 17, S339- S345.

[5]   Alves, L., Correia, A.S.A., Miguel, R., Alegria, P. and Bugalho, P. (2012) Alzheimer’s Disease: A Clinical Practice- Oriented Review. Frontiers in Neurology, 3, 63. http://dx.doi.org/10.3389/fneur.2012.00063

[6]   Bartus, R.T., Dean, R.L., Beer, B. and Lippa, A.S. (1982) The Cholinergic Hypothesis of Geriatric Memory Dysfunction. Science, 217, 408-414. http://dx.doi.org/10.1126/science.7046051

[7]   Whitehouse, P.J., et al. (1982) Alzheimer’s Disease and Senile Dementia: Loss of Neurons in the Basal Forebrain. Science, 215, 1237-1239. http://dx.doi.org/10.1126/science.7058341

[8]   Sweeney, J.E., Puttfarcken, P.S. and Coyle, J.T. (1989) Galanthamine, an Acetylcholinesterase Inhibitor: A Time Course of the Effects on Performance and Neurochemical Parameters in Mice. Pharmacology, Biochemistry, and Behavior, 34, 129-137. http://dx.doi.org/10.1016/0091-3057(89)90364-X

[9]   Zhang, L., Zhou, F.M. and Dani, J.A. (2004) Cholinergic Drugs for Alzheimer’s Disease Enhance in Vitro Dopamine Release. Molecular Pharmacology, 66, 538-544. http://dx.doi.org/10.1124/mol.104.000299

[10]   Lilienfeld, S. (2002) Galantamine—A Novel Cholinergic Drug with a Unique Dual Mode of Action for the Treatment of Patients with Alzheimer’s Disease. CNS Drug Reviews, 8, 159-176.
http://dx.doi.org/10.1111/j.1527-3458.2002.tb00221.x

[11]   Akk, G. (2005) Galantamine Activates Muscle-Type Nicotinic Acetylcholine Receptors without Binding to the Acetylcholine-Binding Site. Journal of Neuroscience, 25, 1992-2001.
http://dx.doi.org/10.1523/JNEUROSCI.4985-04.2005

[12]   Hansen, S.B. and Taylor, P. (2007) Galanthamine and Non-Competitive Inhibitor Binding to ACh-Binding Protein: Evidence for a Binding Site on Non-Alpha-Subunit Interfaces of Heteromeric Neuronal Nicotinic Receptors. Journal of Molecular Biology, 369, 895-901. http://dx.doi.org/10.1016/j.jmb.2007.03.067

[13]   Samochocki, M. (2003) Galantamine Is an Allosterically Potentiating Ligand of Neuronal Nicotinic but Not of Muscarinic Acetylcholine Receptors. Journal of Pharmacology and Experimental Therapeutics, 305, 1024-1036. http://dx.doi.org/10.1124/jpet.102.045773

[14]   Lanctot, K.L., Rajaram, R.D. and Herrmann, N. (2009) Review: Therapy for Alzheimer’s Disease: How Effective Are Current Treatments? Therapeutic Advances in Neurological Disorders, 2, 163-180.
http://dx.doi.org/10.1177/1756285609102724

[15]   Cacabelos, R. (2007) Donepezil in Alzheimer’s Disease: From Conventional Trials to Pharmacogenetics. Neuropsychiatric Disease and Treatment, 3, 303-333.

[16]   Kryger, G., Silman, I. and Sussman, J.L. (1999) Structure of Acetylcholinesterase Complexed with E2020 (Aricept): Implications for the Design of New Anti-Alzheimer Drugs. Structure, 7, 297-307.
http://dx.doi.org/10.1016/S0969-2126(99)80040-9

[17]   Wilkinson, D.G., Francis, P.T., Schwam, E. and Payne-Parrish, J. (2004) Cholinesterase Inhibitors Used in the Treatment of Alzheimer’s Disease: The Relationship between Pharmacological Effects and Clinical Efficacy. Drugs & Aging, 21, 453-478. http://dx.doi.org/10.2165/00002512-200421070-00004

[18]   Jann, M.W. (2000) Rivastigmine, a New-Generation Cholinesterase Inhibitor for the Treatment of Alzheimer’s Disease. Pharmacotherapy, 20, 1-12. http://dx.doi.org/10.1592/phco.20.1.1.34664

[19]   Hansen, R.A., et al. (2008) Efficacy and Safety of Donepezil, Galantamine, and Rivastigmine for the Treatment of Alzheimer’s Disease: A Systematic Review and Meta-Analysis. Clinical Interventions in Aging, 3, 21-225.

[20]   Winblad, B. and Jelic, V. (2004) Long-Term Treatment of Alzheimer Disease: Efficacy and Safety of Acetylcholinesterase Inhibitors. Alzheimer Disease and Associated Disorders, 18, S2-S8.
http://dx.doi.org/10.1097/01.wad.0000127495.10774.a4

[21]   Rogawski, M.A. and Wenk, G.L. (2003) The Neuropharmacological Basis for the Use of Memantine in the Treatment of Alzheimer’s Disease. CNS Drug Reviews, 9, 275-308.
http://dx.doi.org/10.1111/j.1527-3458.2003.tb00254.x

[22]   Aracava, Y., Pereira, E.F.R., Maelicke, A. and Albuquerque, E.X. (2005) Memantine Blocks Alpha7* Nicotinic Acetylcholine Receptors More Potently than N-Methyl-D-aspartate Receptors in Rat Hippocampal Neurons. The Journal of Pharmacology and Experimental Therapeutics, 312, 1195-1205.
http://dx.doi.org/10.1124/jpet.104.077172

[23]   Winblad, B. and Poritis, N. (1999) Memantine in Severe Dementia: Results of the 9M-Best Study (Benefit and Efficacy in Severely Demented Patients during Treatment with Memantine). International Journal of Geriatric Psychiatry, 14, 135-146.
http://dx.doi.org/10.1002/(SICI)1099-1166(199902)14:2<135::AID-GPS906>3.0.CO;2-0

[24]   Tampi, R.R. and van Dyck, C.H. (2007) Memantine: Efficacy and Safety in Mild-to-Severe Alzheimer’s Disease. Neuropsychiatric Disease and Treatment, 3, 245-258.
http://dx.doi.org/10.2147/nedt.2007.3.2.245

[25]   Wang, Z., et al. (2009) Presynaptic and Postsynaptic Interaction of the Amyloid Precursor Protein Promotes Peripheral and Central Synaptogenesis. The Journal of Neuroscience, 29, 10788-10801. http://dx.doi.org/10.1523/JNEUROSCI.2132-09.2009

[26]   Karran, E., Mercken, M. and Strooper, B.D. (2011) The Amyloid Cascade Hypothesis for Alzheimer’s Disease: An Appraisal for the Development of Therapeutics. Nature Reviews Drug Discovery, 10, 698-712. http://dx.doi.org/10.1038/nrd3505

[27]   Murphy, M.P. and LeVine, H. (2010) Alzheimer’s Disease and the Amyloid-Beta Peptide. Journal of Alzheimer’s Disease, 19, 311-323. http://dx.doi.org/10.3233/JAD-2010-1221

[28]   O’Brien, R.J. and Wong, P.C. (2011) Amyloid Precursor Protein Processing and Alzheimer’s Disease. Annual Review of Neuroscience, 34, 185-204. http://dx.doi.org/10.1146/annurev-neuro-061010-113613

[29]   Thinakaran, G. and Koo, E.H. (2008) Amyloid Precursor Protein Trafficking, Processing, and Function. The Journal of Biological Chemistry, 283, 29615-29619. http://dx.doi.org/10.1074/jbc.R800019200

[30]   Roberson, E.D. and Mucke, L. (2006) 100 Years and Counting: Prospects for Defeating Alzheimer’s Disease. Science, 314, 781-784. http://dx.doi.org/10.1126/science.1132813

[31]   Shao, H., Jao, S., Ma, K. and Zagorski, M.G. (1999) Solution Structures of Micelle-Bound Amyloid Beta-(1-40) and Beta-(1-42) Peptides of Alzheimer’s Disease. Journal of Molecular Biology, 285, 755-773. http://dx.doi.org/10.1006/jmbi.1998.2348

[32]   Schmidt, M., et al. (2009) Comparison of Alzheimer Aβ (1-40) and Aβ (1-42) Amyloid Fibrils Reveals Similar Protofilament Structures. Proceedings of the National Academy of Sciences of the United States of America, 106, 19813- 19818. http://dx.doi.org/10.1073/pnas.0905007106

[33]   Sgourakis, N.G., Yan, Y., McCallum, S.A., Wang, C. and Garcia, A.E. (2007) The Alzheimer’s Peptides Aβ40 and 42 Adopt Distinct Conformations in Water: A Combined MD/NMR Study. Journal of Molecular Biology, 368, 1448- 1457. http://dx.doi.org/10.1016/j.jmb.2007.02.093

[34]   Winkler, E., et al. (2012) Generation of Alzheimer Disease-Associated Amyloid β42/43 Peptide by γ-Secretase Can Be Inhibited Directly by Modulation of Membrane Thickness. The Journal of Biological Chemistry, 287, 21326-21334. http://dx.doi.org/10.1074/jbc.M112.356659

[35]   Tyler, S.J., Dawbarn, D., Wilcock, G.K. and Allen, S.J. (2002) Alpha- and Beta-Secretase: Profound Changes in Alzheimer’s Disease. Biochemical and Biophysical Research Communications, 299, 373-376. http://dx.doi.org/10.1016/S0006-291X(02)02635-9

[36]   Finder, V.H. and Glockshuber, R. (2007) Amyloid-Beta Aggregation. Neuro-Degenerative Diseases, 4, 13-27. http://dx.doi.org/10.1159/000100355

[37]   Cohen, S.I.A., et al. (2013) Proliferation of Amyloid-β42 Aggregates Occurs through a Secondary Nucleation Mechanism. Proceedings of the National Academy of Sciences of the United States of America, 110, 9758-9763. http://dx.doi.org/10.1073/pnas.1218402110

[38]   Nestler, E.J. (2009) Molecular Neuropharmacology: A Foundation for Clinical Neuroscience. 2nd Edition, McGraw- Hill Medical, New York.

[39]   Hersh, L.B. and Rodgers, D.W. (2008) Neprilysin and Amyloid Beta Peptide Degradation. Current Alzheimer Research, 5, 225-231. http://dx.doi.org/10.2174/156720508783954703

[40]   Farris, W., et al. (2003) Insulin-Degrading Enzyme Regulates the Levels of Insulin, Amyloid Beta-Protein, and the Beta-Amyloid Precursor Protein Intracellular Domain in Vivo. Proceedings of the National Academy of Sciences of the United States of America, 100, 4162-4167.
http://dx.doi.org/10.1073/pnas.0230450100

[41]   Deane, R., Bell, R.D., Sagare, A. and Zlokovic, B.V. (2009) Clearance of Amyloid-Beta Peptide across the Blood- Brain Barrier: Implication for Therapies in Alzheimer’s Disease. CNS & Neurological Disorders Drug Targets, 8, 16- 30. http://dx.doi.org/10.2174/187152709787601867

[42]   De Strooper, B. (2007) Loss-of-Function Presenilin Mutations in Alzheimer Disease. Talking Point on the Role of Presenilin Mutations in Alzheimer Disease. EMBO Reports, 8, 141-146.
http://dx.doi.org/10.1038/sj.embor.7400897

[43]   Leverenz, J.B., et al. (2006) Lewy Body Pathology in Familial Alzheimer Disease: Evidence for Disease- and Mutation-Specific Pathologic Phenotype. Archives of Neurology, 63, 370-376.
http://dx.doi.org/10.1001/archneur.63.3.370

[44]   Kowalska, A. (2003) Amyloid Precursor Protein Gene Mutations Responsible for Early-Onset Autosomal Dominant Alzheimer’s Disease. Folia Neuropathologica, 41, 35-40.

[45]   Theuns, J., et al. (2006) Promoter Mutations That Increase Amyloid Precursor-Protein Expressed Are Associated with Alzheimer Disease. American Journal of Human Genetics, 78, 936-946.
http://dx.doi.org/10.1086/504044

[46]   Jiang, Q., et al. (2008) ApoE Promotes the Proteolytic Degradation of Aβ. Neuron, 58, 681-693. http://dx.doi.org/10.1016/j.neuron.2008.04.010

[47]   Holmes, C. (2002) Genotype and Phenotype in Alzheimer’s Disease. The British Journal of Psychiatry, 180, 131-134. http://dx.doi.org/10.1192/bjp.180.2.131

[48]   Crump, C.J., Johnson, D.S. and Li, Y.M. (2013) Development and Mechanism of γ-Secretase Modulators for Alzheimer’s Disease. Biochemistry, 52, 3197-3216. http://dx.doi.org/10.1021/bi400377p

[49]   Wolfe, M.S. (2010) Structure, Mechanism and Inhibition of Gamma-Secretase and Presenilin-Like Proteases. Biological Chemistry, 391, 839-847. http://dx.doi.org/10.1515/bc.2010.086

[50]   Ghezzi, L., Scarpini, E. and Galimberti, D. (2013) Disease-Modifying Drugs in Alzheimer’s Disease. Drug Design, Development and Therapy, 7, 1471-1478. http://dx.doi.org/10.2147/DDDT.S41431

[51]   Fortini, M.E. (2001) Notch and Presenilin: A Proteolytic Mechanism Emerges. Current Opinion in Cell Biology, 13, 627-634. http://dx.doi.org/10.1016/S0955-0674(00)00261-1

[52]   De Strooper, B., et al. (1999) A Presenilin-1-Dependent Gamma-Secretase-Like Protease Mediates Release of Notch Intracellular Domain. Nature, 398, 518-522. http://dx.doi.org/10.1038/19083

[53]   Krop, I., et al. (2012) Phase I Pharmacologic and Pharmacodynamic Study of the Gamma Secretase (Notch) Inhibitor MK-0752 in Adult Patients with Advanced Solid Tumors. Journal of Clinical Oncology, 30, 2307-2313. http://dx.doi.org/10.1200/JCO.2011.39.1540

[54]   Hajós, M., et al. (2013) Effects of the γ-Secretase Inhibitor Semagacestat on Hippocampal Neuronal Network Oscillation. Frontiers in Pharmacology, 4, 72. http://dx.doi.org/10.3389/fphar.2013.00072

[55]   Redmond, L., Oh, S.R., Hicks, C., Weinmaster, G. and Ghosh, A. (2000) Nuclear Notch1 Signaling and the Regulation of Dendritic Development. Nature Neuroscience, 3, 30-40. http://dx.doi.org/10.1038/71104

[56]   Huang, E.J., et al. (2005) Targeted Deletion of Numb and Numblike in Sensory Neurons Reveals Their Essential Functions in Axon Arborization. Genes & Development, 19, 138-151.
http://dx.doi.org/10.1101/gad.1246005

[57]   Wakabayashi, T. and De Strooper, B. (2008) Presenilins: Members of the γ-Secretase Quartets, But Part-Time Soloists Too. Physiology, 23, 194-204. http://dx.doi.org/10.1152/physiol.00009.2008

[58]   Coric, V., et al. (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.
http://dx.doi.org/10.1001/archneurol.2012.2194

[59]   Beher, D., et al. (2004) Selected Non-Steroidal Anti-Inflammatory Drugs and Their Derivatives Target Gamma- Secretase at a Novel Site. Evidence for an Allosteric Mechanism. The Journal of Biological Chemistry, 279, 43419- 43426. http://dx.doi.org/10.1074/jbc.M404937200

[60]   Kukar, T.L., et al. (2008) Substrate-Targeting Gamma-Secretase Modulators. Nature, 453, 925-929. http://dx.doi.org/10.1038/nature07055

[61]   Green, R.C., et al. (2009) Effect of Tarenflurbil on Cognitive Decline and Activities of Daily Living in Patients with Mild Alzheimer Disease: A Randomized Controlled Trial. Journal of the American Medical Association, 302, 2557- 2564. http://dx.doi.org/10.1001/jama.2009.1866

[62]   Galasko, D.R., et al. (2007) Safety, Tolerability, Pharmacokinetics, and ABeta Levels after Short-Term Administration of R-Flurbiprofen in Healthy Elderly Individuals. Alzheimer Disease and Associated Disorders, 21, 292-299. http://dx.doi.org/10.1097/WAD.0b013e31815d1048

[63]   Tate, B., et al. (2012) Modulation of Gamma-Secretase for the Treatment of Alzheimer’s Disease. International Journal of Alzheimer’s Disease, 2012, 210756. http://dx.doi.org/10.1155/2012/210756

[64]   Ghosh, A.K., Brindisi, M. and Tang, J. (2012) Developing β-Secretase Inhibitors for Treatment of Alzheimer’s Disease. Journal of Neurochemistry, 120, 71-83.
http://dx.doi.org/10.1111/j.1471-4159.2011.07476.x

[65]   Lahiri, D.K., Maloney, B., Long, J.M. and Greig, N.H. (2014) Lessons from a BACE1 Inhibitor Trial: Off-Site but Not off Base. Alzheimer’s & Dementia, in press. http://dx.doi.org/10.1016/j.jalz.2013.11.004

[66]   Zhu, Z., et al. (2010) 2,2’,4’-Trihydroxychalcone from Glycyrrhiza glabra as a New Specific BACE1 Inhibitor Efficiently Ameliorates Memory Impairment in Mice. Journal of Neurochemistry, 114, 374-385. http://dx.doi.org/10.1111/j.1471-4159.2010.06751.x

[67]   Roberds, S.L., et al. (2001) BACE Knockout Mice Are Healthy despite Lacking the Primary Beta-Secretase Activity in Brain: Implications for Alzheimer’s Disease Therapeutics. Human Molecular Genetics, 10, 1317-1324. http://dx.doi.org/10.1093/hmg/10.12.1317

[68]   Kobayashi, D., et al. (2008) BACE1 Gene Deletion: Impact on Behavioral Function in a Model of Alzheimer’s Disease. Neurobiology of Aging, 29, 861-873.
http://dx.doi.org/10.1016/j.neurobiolaging.2007.01.002

[69]   Willem, M., et al. (2006) Control of Peripheral Nerve Myelination by the Beta-Secretase BACE1. Science, 314, 664- 666. http://dx.doi.org/10.1126/science.1132341

[70]   Rajapaksha, T.W., Eimer, W.A., Bozza, T.C. and Vassar, R. (2011) The Alzheimer’s β-Secretase Enzyme BACE1 Is Required for Accurate Axon Guidance of Olfactory Sensory Neurons and Normal Glomerulus Formation in the Olfactory Bulb. Molecular Neurodegeneration, 6, 88.
http://dx.doi.org/10.1186/1750-1326-6-88

[71]   Fu, H.J., Liu, B., Frost, J.L. and Lemere, C.A. (2010) Amyloid-Beta Immunotherapy for Alzheimer’s Disease. CNS & Neurological Disorders Drug Targets, 9, 197-206.
http://dx.doi.org/10.2174/187152710791012017

[72]   Schenk, D., et al. (1999) Immunization with Amyloid-Beta Attenuates Alzheimer-Disease-Like Pathology in the PDAPP Mouse. Nature, 400, 173-177. http://dx.doi.org/10.1038/22124

[73]   Gilman, S., et al. (2005) Clinical Effects of ABeta Immunization (AN1792) in Patients with AD in an Interrupted Trial. Neurology, 64, 1553-1562. http://dx.doi.org/10.1212/01.WNL.0000159740.16984.3C

[74]   Keller, D.M. (2013) Alzheimer’s Vaccine Shows Efficacy without Adverse Effects. Alzheimer’s Disease International (ADI) 28th International Conference, Taipei, 22 April 2013, OC025.

[75]   Plotkin, S.A., Orenstein, W.A. and Offit, P.A. (2013) Vaccines. 6th Edition, Elsevier Saunders, Philadelphia.

[76]   Kerchner, G.A. and Boxer, A.L. (2010) Bapineuzumab. Expert Opinion on Biological Therapy, 10, 1121-1130. http://dx.doi.org/10.1517/14712598.2010.493872

[77]   Morgan, D., et al. (2000) A Beta Peptide Vaccination Prevents Memory Loss in an Animal Model of Alzheimer’s Disease. Nature, 408, 982-985. http://dx.doi.org/10.1038/35050116

[78]   Lombardo, J.A., et al. (2003) Amyloid-Beta Antibody Treatment Leads to Rapid Normalization of Plaque-Induced Neuritic Alterations. The Journal of Neuroscience, 23, 10879-10883.

[79]   Moreth, J., Mavoungou, C. and Schindowski, K. (2013) Passive Anti-Amyloid Immunotherapy in Alzheimer’s Disease: What Are the Most Promising Targets? Immunity & Ageing, 10, 18.
http://dx.doi.org/10.1186/1742-4933-10-18

[80]   Castellani, R.J. and Smith, M.A. (2011) Compounding Artefacts with Uncertainty, and an Amyloid Cascade Hypothesis That Is “Too Big to Fail”. The Journal of Pathology, 224, 147-152.
http://dx.doi.org/10.1002/path.2885

[81]   Teich, A.F. and Arancio, O. (2012) Is the Amyloid Hypothesis of Alzheimer’s Disease Therapeutically Relevant? The Biochemical Journal, 446, 165-177. http://dx.doi.org/10.1042/BJ20120653

[82]   Ballatore, C., Lee, V.M.Y. and Trojanowski, J.Q. (2007) Tau-Mediated Neurodegeneration in Alzheimer’s Disease and Related Disorders. Nature Reviews Neuroscience, 8, 663-672.
http://dx.doi.org/10.1038/nrn2194

[83]   Brunden, K.R., Trojanowski, J.Q. and Lee, V.M.Y. (2009) Advances in Tau-Focused Drug Discovery for Alzheimer’s Disease and Related Tauopathies. Nature Reviews Drug Discovery, 8, 783-793.
http://dx.doi.org/10.1038/nrd2959

[84]   Mohandas, E., Rajmohan, V., and Raghunath, B. (2009) Neurobiology of Alzheimer’s Disease. Indian Journal of Psychiatry, 51, 55. http://dx.doi.org/10.4103/0019-5545.44908

[85]   Bunker, J.M. (2004) Modulation of Microtubule Dynamics by Tau in Living Cells: Implications for Development and Neurodegeneration. Molecular Biology of the Cell, 15, 2720-2728.
http://dx.doi.org/10.1091/mbc.E04-01-0062

[86]   Butner, K.A. and Kirschner, M.W. (1991) Tau Protein Binds to Microtubules through a Flexible Array of Distributed Weak Sites. The Journal of Cell Biology, 115, 717-730.
http://dx.doi.org/10.1083/jcb.115.3.717

[87]   Johnson, G.V.W. and Stoothoff, W.H. (2004) Tau Phosphorylation in Neuronal Cell Function and Dysfunction. Journal of Cell Science, 117, 5721-5729. http://dx.doi.org/10.1242/jcs.01558

[88]   Alonso. A, Li, B., Grundke-Iqbal, I. and Iqbal, K. (2006) Polymerization of Hyperphosphorylated Tau into Filaments Eliminates Its Inhibitory Activity. Proceedings of the National Academy of Sciences of the United States of America, 103, 8864-8869. http://dx.doi.org/10.1073/pnas.0603214103

[89]   Wang, J.Z., Xia, Y.Y., Grundke-Iqbal, I. and Iqbal, K. (2013) Abnormal Hyperphosphorylation of Tau: Sites, Regulation, and Molecular Mechanism of Neurofibrillary Degeneration. Journal of Alzheimer’s Disease, 33, S123-S139. http://dx.doi.org/10.3233/JAD-2012-129031

[90]   Buée, L., Bussière, T., Buée-Scherrer, V., Delacourte, A. and Hof, P.R. (2000) Tau Protein Isoforms, Phosphorylation and Role in Neurodegenerative Disorders. Brain Research Reviews, 33, 95-130. http://dx.doi.org/10.1016/S0165-0173(00)00019-9

[91]   Llorens-Martin, M., et al. (2012) Tau Isoform with Three Microtubule Binding Domains Is a Marker of New Axons Generated from the Subgranular Zone in the Hippocampal Dentate Gyrus: Implications for Alzheimer’s Disease. Journal of Alzheimer’s Disease, 29, 921-930.
http://dx.doi.org/10.3233/JAD-2012-112057

[92]   Martin, L., Latypova, X. and Terro, F. (2011) Post-Translational Modifications of Tau Protein: Implications for Alzheimer’s Disease. Neurochemistry International, 58, 458-471.
http://dx.doi.org/10.1016/j.neuint.2010.12.023

[93]   Hanger, D.P., Anderton, B.H. and Noble, W. (2009) Tau Phosphorylation: The Therapeutic Challenge for Neurodegenerative Disease. Trends in Molecular Medicine, 15, 112-119.
http://dx.doi.org/10.1016/j.molmed.2009.01.003

[94]   Trojanowski, J.Q. and Lee, V.M.Y. (2005) Pathological Tau: A Loss of Normal Function or a Gain in Toxicity? Nature Neuroscience, 8, 1136-1137. http://dx.doi.org/10.1038/nn0905-1136

[95]   Morishima-Kawashima, M., et al. (1995) Hyperphosphorylation of Tau in PHF. Neurobiology of Aging, 16, 365-380. http://dx.doi.org/10.1016/0197-4580(95)00027-C

[96]   Hanger, D.P., et al. (2007) Novel Phosphorylation Sites in Tau from Alzheimer Brain Support a Role for Casein Kinase 1 in Disease Pathogenesis. Journal of Biological Chemistry, 282, 23645-23654.
http://dx.doi.org/10.1074/jbc.M703269200

[97]   Vega, I.E., et al. (2005) Increase in Tau Tyrosine Phosphorylation Correlates with the Formation of Tau Aggregates. Molecular Brain Research, 138, 135-144.
http://dx.doi.org/10.1016/j.molbrainres.2005.04.015

[98]   Morishima-Kawashima, M., et al. (1995) Proline-Directed and Non-Proline-Directed Phosphorylation of PHF-Tau. The Journal of Biological Chemistry, 270, 823-829. http://dx.doi.org/10.1074/jbc.270.2.823

[99]   Paudel, H.K, Lew, J., Ali, Z. and Wang, J.H. (1993) Brain Proline-Directed Protein Kinase Phosphorylates Tau on Sites That Are Abnormally Phosphorylated in Tau Associated with Alzheimer’s Paired Helical Filaments. The Journal of Biological Chemistry, 268, 23512-23518.

[100]   Kremer, A., Louis, J.V., Jaworski, T. and Van Leuven, F. (2011) GSK3 and Alzheimer’s Disease: Facts and Fiction…. Frontiers in Molecular Neuroscience, 4, 17. http://dx.doi.org/10.3389/fnmol.2011.00017

[101]   Reynolds, C.H., Betts, J.C, Blackstock, W.P., Nebreda, A.R. and Anderton, B.H. (2000) Phosphorylation Sites on Tau Identified by Nanoelectrospray Mass Spectrometry: Differences in Vitro between the Mitogen-Activated Protein Kinases ERK2, c-Jun N-terminal Kinase and P38, and Glycogen Synthase Kinase-3Beta. Journal of Neurochemistry, 74, 1587-1595. http://dx.doi.org/10.1046/j.1471-4159.2000.0741587.x

[102]   Sironi, J.J., et al. (1998) Ser-262 in Human Recombinant Tau Protein Is a Markedly More Favorable Site for Phosphorylation by CaMKII than PKA or PhK. FEBS letters, 436, 471-475.
http://dx.doi.org/10.1016/S0014-5793(98)01185-5

[103]   Schneider, A., Biernat, J., von Bergen, M., Mandelkow, E. and Mandelkow, E.M. (1999) Phosphorylation That Detaches Tau Protein from Microtubules (Ser262, Ser214) Also Protects It against Aggregation into Alzheimer Paired Helical Filaments. Biochemistry, 38, 3549-3558. http://dx.doi.org/10.1021/bi981874p

[104]   Martin, L., et al. (2013) Tau Protein Phosphatases in Alzheimer’s Disease: The Leading Role of PP2A. Ageing Research Reviews, 12, 39-49. http://dx.doi.org/10.1016/j.arr.2012.06.008

[105]   Hooper, C., et al. (2007) Glycogen Synthase Kinase-3 Inhibition Is Integral to Long-Term Potentiation. The European Journal of Neuroscience, 25, 81-86. http://dx.doi.org/10.1111/j.1460-9568.2006.05245.x

[106]   Dewachter, I., et al. (2009) GSK3Beta, a Centre-Staged Kinase in Neuropsychiatric Disorders, Modulates Long Term Memory by Inhibitory Phosphorylation at Serine-9. Neurobiology of Disease, 35, 193-200. http://dx.doi.org/10.1016/j.nbd.2009.04.003

[107]   Chen, P., Gu, Z., Liu, W. and Yan, Z. (2007) Glycogen Synthase Kinase 3 Regulates N-Methyl-D-aspartate Receptor Channel Trafficking and Function in Cortical Neurons. Molecular Pharmacology, 72, 40-51. http://dx.doi.org/10.1124/mol.107.034942

[108]   Decker, H., Lom, K.Y., Unger, S.M., Ferreira, S.T. and Silverman, M.A. (2010) Amyloid-Beta Peptide Oligomers Disrupt Axonal Transport through an NMDA Receptor-Dependent Mechanism That Is Mediated by Glycogen Synthase kinase 3Beta in Primary Cultured Hippocampal Neurons. The Journal of Neuroscience, 30, 9166-9171. http://dx.doi.org/10.1523/JNEUROSCI.1074-10.2010

[109]   Leroy, K., Yilmaz, Z. and Brion, J.P. (2007) Increased Level of Active GSK-3Beta in Alzheimer’s Disease and Accumulation in Argyrophilic Grains and in Neurons at Different Stages of Neurofibrillary Degeneration. Neuropathology and Applied Neurobiology, 33, 43-55.
http://dx.doi.org/10.1111/j.1365-2990.2006.00795.x

[110]   Terwel, D., et al. (2008) Amyloid Activates GSK-3Beta to Aggravate Neuronal Tauopathy in BigenicMice. The American Journal of Pathology, 172, 786-798. http://dx.doi.org/10.2353/ajpath.2008.070904

[111]   Braak, H. and Del Tredici, K. (2012) Where, When, and in What Form Does Sporadic Alzheimer’s Disease Begin? Current Opinion in Neurology, 25, 708-714. http://dx.doi.org/10.1097/WCO.0b013e32835a3432

[112]   Mann, D.M.A. and Hardy, J. (2013) Amyloid or Tau: The Chicken or the Egg? Acta Neuropathologica, 126, 609-613. http://dx.doi.org/10.1007/s00401-013-1162-1

[113]   Roberson, E.D., et al. (2007) Reducing Endogenous Tau Ameliorates Amyloid Beta-Induced Deficits in an Alzheimer’s Disease Mouse Model. Science, 316, 750-754. http://dx.doi.org/10.1126/science.1141736

[114]   Ittner, L.M., et al. (2010) Dendritic Function of Tau Mediates Amyloid-Beta Toxicity in Alzheimer’s Disease Mouse Models. Cell, 142, 387-397. http://dx.doi.org/10.1016/j.cell.2010.06.036

[115]   Vossel, K.A., et al. (2010) Tau Reduction Prevents Abeta-Induced Defects in Axonal Transport. Science, 330, 198. http://dx.doi.org/10.1126/science.1194653

[116]   Gong, C.X., Singh, T.J., Grundke-Iqbal, I. and Iqbal, K. (1993) Phosphoprotein Phosphatase Activities in Alzheimer Disease Brain. Journal of Neurochemistry, 61, 921-927.
http://dx.doi.org/10.1111/j.1471-4159.1993.tb03603.x

[117]   Vogelsberg-Ragaglia, V., Schuck, T., Trojanowski, J.Q. and Lee, V.M. (2001) PP2A mRNA Expression Is Quantitatively Decreased in Alzheimer’s Disease Hippocampus. Experimental Neurology, 168, 402-412. http://dx.doi.org/10.1006/exnr.2001.7630

[118]   Wang, J.Z., Grundke-Iqbal, I. and Iqbal, K. (2007) Kinases and Phosphatases and Tau Sites Involved in Alzheimer Neurofibrillary Degeneration. The European Journal of Neuroscience, 25, 59-68.
http://dx.doi.org/10.1111/j.1460-9568.2006.05226.x

[119]   Sontag, E., et al. (2004) Downregulation of Protein Phosphatase 2A Carboxyl Methylation and Methyltransferase May Contribute to Alzheimer Disease Pathogenesis. Journal of Neuropathology and Experimental Neurology, 63, 1080- 1091.

[120]   Sontag, J.M. and Sontag, E. (2014) Protein Phosphatase 2A Dysfunction in Alzheimer’s Disease. Frontiers in Molecular Neuroscience, 7, 16. http://dx.doi.org/10.3389/fnmol.2014.00016

[121]   Jordens, J., et al. (2006) The Protein Phosphatase 2A Phosphatase Activator Is a Novel Peptidyl-Prolylcis/Trans- Isomerase. Journal of Biological Chemistry, 281, 6349-6357.
http://dx.doi.org/10.1074/jbc.M507760200

[122]   Wang, J.Z., Grundke-Iqbal, I. and Iqbal, K. (1996) Glycosylation of Microtubule-Associated Protein Tau: An Abnormal Posttranslational Modification in Alzheimer’s Disease. Nature Medicine, 2, 871-875.
http://dx.doi.org/10.1038/nm0896-871

[123]   Takahashi, M., et al. (1999) Glycosylation of Microtubule-Associated Protein Tau in Alzheimer’s Disease Brain. ActaNeuropathologica, 97, 635-641. http://dx.doi.org/10.1007/s004010051040

[124]   Liu, F., et al. (2002) Role of Glycosylation in Hyperphosphorylation of Tau in Alzheimer’s Disease. FEBS Letters, 512, 101-106. http://dx.doi.org/10.1016/S0014-5793(02)02228-7

[125]   Liu, F., Zaidi, T., Iqbal, K., Grundke-Iqbal, I. and Gong, C.X. (2002) Aberrant Glycosylation Modulates Phosphorylation of Tau by Protein Kinase A and Dephosphorylation of Tau by Protein Phosphatase 2A and 5. Neuroscience, 115, 829-837. http://dx.doi.org/10.1016/S0306-4522(02)00510-9

[126]   Liu, F., et al. (2009) Reduced O-GlcNAcylation Links Lower Brain Glucose Metabolism and Tau Pathology in Alzheimer’s Disease. Brain, 132, 1820-1832. http://dx.doi.org/10.1093/brain/awp099

[127]   Robertson, L.A., Moya, K.L. and Breen, K.C. (2004) The Potential Role of Tau Protein O-Glycosylation in Alzheimer’s Disease. Journal of Alzheimer’s Disease, 6, 489-495.

[128]   Yuzwa, S.A., et al. (2012) Increasing O-GlcNAcSlows Neurodegeneration and Stabilizes Tau against Aggregation. Nature Chemical Biology, 8, 393-399. http://dx.doi.org/10.1038/nchembio.797

[129]   Del Ser, T., et al. (2013) Treatment of Alzheimer’s Disease with the GSK-3 Inhibitor Tideglusib: A Pilot Study. Journal of Alzheimer’s Disease, 33, 205-215. http://dx.doi.org/10.3233/JAD-2012-120805

[130]   Alvarez, X.A., et al. (2011) Combination Treatment in Alzheimer’s Disease: Results of a Randomized, Controlled Trial with Cerebrolysin and Donepezil. Current Alzheimer Research, 8, 583-591.
http://dx.doi.org/10.2174/156720511796391863

[131]   Hosokawa, M., et al. (2012) Methylene Blue Reduced Abnormal Tau Accumulation in P301L Tau Transgenic Mice. PLoS ONE, 7, e52389. http://dx.doi.org/10.1371/journal.pone.0052389

[132]   Lira-De León, K.I., et al. (2013) Molecular Mechanism of Tau Aggregation Induced by Anionic and Cationic Dyes. Journal of Alzheimer’s Disease, 35, 319-334. http://dx.doi.org/10.3233/JAD-121765

[133]   Congdon, E.E., et al. (2012) MethylthioniniumChloride (Methylene Blue) Induces Autophagy and Attenuates Tauopathy in Vitro and in Vivo. Autophagy, 8, 609-622. http://dx.doi.org/10.4161/auto.19048

[134]   Wischik, C.M., Bentham, P., Wischik, D.J. and Seng, K.M. (2008) Tau Aggregation Inhibitor (TAI) Therapy with RemberTM Arrests Disease Progression in Mild and Moderate Alzheimer’s Disease over 50 Weeks. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 4, T167.
http://dx.doi.org/10.1016/j.jalz.2008.05.438

[135]   Küçükk¡l¡nç, T. and Özer, Î. (2007) Multi-Site Inhibition of Human Plasma Cholinesterase by Cationic Phenoxazine and Phenothiazine Dyes. Archives of Biochemistry and Biophysics, 461, 294-298.
http://dx.doi.org/10.1016/j.abb.2007.02.029

[136]   Chies, A.B., Custódio, R.C., de Souza, G.L., Corrêa, F.M.A. and Pereira, O.C.M. (2003) Pharmacological Evidence That Methylene Blue Inhibits Noradrenaline Neuronal Uptake in the Rat Vas Deferens. Polish Journal of Pharmacology, 55, 573-579.

[137]   Medina, D.X., Caccamo, A. and Oddo, S. (2011) Methylene Blue Reduces Aβ Levels and Rescues Early Cognitive Deficit by Increasing Proteasome Activity: Methylene Blue Reduces Memory Deficits. Brain Pathology, 21, 140-149. http://dx.doi.org/10.1111/j.1750-3639.2010.00430.x

[138]   Gonzalez-Lima, F. (2004) Extinction Memory Improvement by the Metabolic Enhancer Methylene Blue. Learning & Memory, 11, 633-640. http://dx.doi.org/10.1101/lm.82404

[139]   Wrubel, K.M., Riha, P.D., Maldonado, M.A., McCollum, D. and Gonzalez-Lima, F. (2007) The Brain Metabolic Enhancer Methylene Blue Improves Discrimination Learning in Rats. Pharmacology Biochemistry and Behavior, 86, 712-717. http://dx.doi.org/10.1016/j.pbb.2007.02.018

[140]   Giacobini, E. and Gold, G. (2013) Alzheimer Disease Therapy—Moving from Amyloid-β to Tau. Nature Reviews Neurology, 9, 677-686. http://dx.doi.org/10.1038/nrneurol.2013.223

[141]   Michaelis, M.L., et al. (2005) Beta-Amyloid-Induced Neurodegeneration and Protection by Structurally Diverse Microtubule-Stabilizing Agents. The Journal of Pharmacology and Experimental Therapeutics, 312, 659-668. http://dx.doi.org/10.1124/jpet.104.074450

[142]   Ballatore, C., et al. (2012) Microtubule Stabilizing Agents as Potential Treatment for Alzheimer’s Disease and Related Neurodegenerative Tauopathies. Journal of Medicinal Chemistry, 55, 8979-8996.
http://dx.doi.org/10.1021/jm301079z

[143]   Brunden, K.R., et al. (2011) The Characterization of Microtubule-Stabilizing Drugs as Possible Therapeutic Agents for Alzheimer’s Disease and Related Tauopathies. Pharmacological Research, 63, 341-351. http://dx.doi.org/10.1016/j.phrs.2010.12.002

[144]   Zhang, B., et al. (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 Neuroscience, 32, 3601-3611.
http://dx.doi.org/10.1523/JNEUROSCI.4922-11.2012

[145]   Barten, D.M., et al. (2012) Hyperdynamic Microtubules, Cognitive Deficits, and Pathology Are Improved in Tau Transgenic Mice with Low Doses of the Microtubule-Stabilizing Agent BMS-241027. The Journal of Neuroscience, 32, 7137-7145. http://dx.doi.org/10.1523/JNEUROSCI.0188-12.2012

[146]   Rapoport, S.I., Hatanpää, K., Brady, D.R. and Chandrasekaran, K. (1996) Brain Energy Metabolism, Cognitive Function and Down-Regulated Oxidative Phosphorylation in Alzheimer Disease. Neurodegeneration, 5, 473-476. http://dx.doi.org/10.1006/neur.1996.0065

[147]   Sun, J., Feng, X., Liang, D., Duan, Y. and Lei, H. (2012) Down-Regulation of Energy Metabolism in Alzheimer’s Disease Is a Protective Response of Neurons to the Microenvironment. Journal of Alzheimer’s Disease, 28, 389-402. http://dx.doi.org/10.3233/JAD-2011-111313

[148]   Henderson, S.T., et al. (2009) Study of the Ketogenic Agent AC-1202 in Mild to Moderate Alzheimer’s Disease: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial. Nutrition & Metabolism, 6, 31. http://dx.doi.org/10.1186/1743-7075-6-31

[149]   Meraz-Ríos, M.A., Toral-Rios, D., Franco-Bocanegra, D., Villeda-Hernández, J. and Campos-Peña, V. (2013) Inflammatory Process in Alzheimer’s Disease. Frontiers in Integrative Neuroscience, 7, 59. http://dx.doi.org/10.3389/fnint.2013.00059

[150]   Tuppo, E.E. and Arias, H.R. (2005) The Role of Inflammation in Alzheimer’s Disease. The International Journal of Biochemistry & Cell Biology, 37, 289-305. http://dx.doi.org/10.1016/j.biocel.2004.07.009

[151]   Scheff, S.W., DeKosky, S.T. and Price, D.A. (1990) Quantitative Assessment of Cortical Synaptic Density in Alzheimer’s Disease. Neurobiology of Aging, 11, 29-37.
http://dx.doi.org/10.1016/0197-4580(90)90059-9

[152]   Scheff, S.W. and Price, D.A. (1993) Synapse Loss in the Temporal Lobe in Alzheimer’s Disease. Annals of Neurology, 33, 190-199. http://dx.doi.org/10.1002/ana.410330209

[153]   Henneman, W.J.P., et al. (2009) Hippocampal Atrophy Rates in Alzheimer Disease: Added Value over Whole Brain Volume Measures. Neurology, 72, 999-1007.
http://dx.doi.org/10.1212/01.wnl.0000344568.09360.31

[154]   Davies, P. and Maloney, A.J. (1976) Selective Loss of Central Cholinergic Neurons in Alzheimer’s Disease. The Lancet, 2, 1403. http://dx.doi.org/10.1016/S0140-6736(76)91936-X

[155]   McGleenon, Dynan and Passmore. (2001) Acetylcholinesterase Inhibitors in Alzheimer’s Disease. British Journal of Clinical Pharmacology, 48, 471-480. http://dx.doi.org/10.1046/j.1365-2125.1999.00026.x

[156]   Donev, R., Kolev, M., Millet, B. and Thome, J. (2009) Neuronal Death in Alzheimer’s Disease and Therapeutic Opportunities. Journal of Cellular and Molecular Medicine, 13, 4329-4348.
http://dx.doi.org/10.1111/j.1582-4934.2009.00889.x

[157]   Sugimoto, T., et al. (2001) Signal Transduction Pathways through TRK-A and TRK-B Receptors in Human Neuroblastoma Cells. Japanese Journal of Cancer Research, 92, 152-160.
http://dx.doi.org/10.1111/j.1349-7006.2001.tb01077.x

[158]   Aksamitiene, E., Kiyatkin, A. and Kholodenko, B.N. (2012) Cross-Talk between Mitogenic Ras/MAPK and Survival PI3K/Akt Pathways: A Fine Balance. Biochemical Society Transactions, 40, 139-146.
http://dx.doi.org/10.1042/BST20110609

[159]   McCubrey, J.A., et al. (2012) Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascade Inhibitors: How Mutations Can Result in Therapy Resistance and How to Overcome Resistance. Oncotarget, 3, 1068-1111.

[160]   Castellano, E. and Downward, J. (2011) RAS Interaction with PI3K: More than Just Another Effector Pathway. Genes & Cancer, 2, 261-274. http://dx.doi.org/10.1177/1947601911408079

[161]   Saini, H.S., Gorse, K.M., Boxer, L.M. and Sato-Bigbee, C. (2004) Neurotrophin-3 and a CREB-Mediated Signaling Pathway Regulate Bcl-2 Expression in Oligodendrocyte Progenitor Cells. Journal of Neurochemistry, 89, 951-961. http://dx.doi.org/10.1111/j.1471-4159.2004.02365.x

[162]   Chang, F., et al. (2003) Signal Transduction Mediated by the Ras/Raf/MEK/ERK Pathway from Cytokine Receptors to Transcription Factors: Potential Targeting for Therapeutic Intervention. Leukemia, 17, 1263-1293. http://dx.doi.org/10.1038/sj.leu.2402945

[163]   Kaplan, D.R. and Miller, F.D. (2000) Neurotrophin Signal Transduction in the Nervous System. Current Opinion in Neurobiology, 10, 381-391. http://dx.doi.org/10.1016/S0959-4388(00)00092-1

[164]   McCubrey, J.A., et al. (2007) Roles of the Raf/MEK/ERK Pathway in Cell Growth, Malignant Transformation and Drug Resistance. Biochimica et Biophysica Acta-Molecular Cell Research, 1773, 1263-1284. http://dx.doi.org/10.1016/j.bbamcr.2006.10.001

[165]   Shonai, T., et al. (2002) MEK/ERK Pathway Protects Ionizing Radiation-Induced Loss of Mitochondrial Membrane Potential and Cell Death in Lymphocytic Leukemia Cells. Cell Death and Differentiation, 9, 963-971. http://dx.doi.org/10.1038/sj.cdd.4401050

[166]   McCubrey, J.A., et al. (2007) Critical Roles of the Raf/MEK/ERK Pathway in Apoptosis and Drug Resistance. In: Srivastava, R., Ed., Apoptosis, Cell Signaling, and Human Diseases, Humana Press, Totowa, 101-134. http://dx.doi.org/10.1007/978-1-59745-199-4_5

[167]   Koliatsos, V.E., et al. (1990) Mouse Nerve Growth Factor Prevents Degeneration of Axotomized Basal Forebrain Cholinergic Neurons in the Monkey. The Journal of Neuroscience, 10, 3801-3813.

[168]   Koliatsos, V.E., et al. (1991) Human Nerve Growth Factor Prevents Degeneration of Basal Forebrain Cholinergic Neurons in Primates. Annals of Neurology, 30, 831-840.
http://dx.doi.org/10.1002/ana.410300613

[169]   Tuszynski, M.H., Sang, U.H., Yoshida, K. and Gage, F.H. (1991) Recombinant Human Nerve Growth Factor Infusions Prevent Cholinergic Neuronal Degeneration in the Adult Primate Brain. Annals of Neurology, 30, 625-636. http://dx.doi.org/10.1002/ana.410300502

[170]   Rafii, M.S., et al. (2014) A Phase1 Study of Stereotactic Gene Delivery of AAV2-NGF for Alzheimer’s Disease. Alzheimer’s & Dementia, in press. http://dx.doi.org/10.1016/j.jalz.2013.09.004

[171]   Kita, T., et al. (1998) Scabronines B, C, D, E and F, Novel Diterpenoids Showing Stimulating Activity of Nerve Growth Factor-Synthesis, from the Mushroom Sarcodon scabrosus. Tetrahedron, 54, 11877-11886. http://dx.doi.org/10.1016/S0040-4020(98)83045-7

[172]   Kawagishi, H., et al. (1996) Erinacines E, F, and G, Stimulators of Nerve Growth Factor (NGF)-Synthesis, from the Mycelia of Hericium erinaceum. Tetrahedron Letters, 37, 7399-7402.
http://dx.doi.org/10.1016/0040-4039(96)01687-5

[173]   Mori, K., et al. (2008) Nerve Growth Factor-Inducing Activity of Hericium erinaceus in 1321N1 Human Astrocytoma Cells. Biological & Pharmaceutical Bulletin, 31, 1727-1732.
http://dx.doi.org/10.1248/bpb.31.1727

[174]   Dixon, E., et al. (2010) Bacteria-Induced Static Batch Fungal Fermentation of the Diterpenoid Cyathin A3, a Small- Molecule Inducer of Nerve Growth Factor. Journal of Industrial Microbiology & Biotechnology, 38, 607-615. http://dx.doi.org/10.1007/s10295-010-0805-7

[175]   Finkbeiner, S., et al. (1997) CREB: A Major Mediator of Neuronal Neurotrophin Responses. Neuron, 19, 1031-1047. http://dx.doi.org/10.1016/S0896-6273(00)80395-5

[176]   García-Osta, A., Cuadrado-Tejedor, M., García-Barroso, C., Oyarzábal, J. and Franco, R. (2012) Phosphodiesterases as Therapeutic Targets for Alzheimer’s Disease. ACS Chemical Neuroscience, 3, 832-844. http://dx.doi.org/10.1021/cn3000907

[177]   Bernabeu, R., et al. (1997) Involvement of Hippocampal cAMP/cAMP-Dependent Protein Kinase Signaling Pathways in a Late Memory Consolidation Phase of Aversively Motivated Learning in Rats. Proceedings of the National Academy of Sciences of the United States of America, 94, 7041-7046.
http://dx.doi.org/10.1073/pnas.94.13.7041

[178]   Abel, T., et al. (1997) Genetic Demonstration of a Role for PKA in the Late Phase of LTP and in Hippocampus-Based Long-Term Memory. Cell, 88, 615-626.
http://dx.doi.org/10.1016/S0092-8674(00)81904-2

[179]   Kimura, S., Uchiyama, S., Takahashi, H.E. and Shibuki, K. (1998) cAMP-Dependent Long-Term Potentiation of Nitric Oxide Release from Cerebellar Parallel Fibers in Rats. The Journal of Neuroscience, 18, 8551-8558.

[180]   Matsumoto, Y., Unoki, S., Aonuma, H. and Mizunami, M. (2006) Critical Role of Nitric Oxide-cGMP Cascade in the Formation of cAMP-Dependent Long-Term Memory. Learning & Memory, 13, 35-44.
http://dx.doi.org/10.1101/lm.130506

[181]   Puzzo, D., et al. (2009) Phosphodiesterase 5 Inhibition Improves Synaptic Function, Memory, and Amyloid-Beta Load in an Alzheimer’s Disease Mouse Model. The Journal of Neuroscience, 29, 8075-8086. http://dx.doi.org/10.1523/JNEUROSCI.0864-09.2009

[182]   Sierksma, A.S.R., et al. (2013) Chronic Phosphodiesterase Type 2 Inhibition Improves Memory in the APPswe/ PS1dE9 Mouse Model of Alzheimer’s Disease. Neuropharmacology, 64, 124-136.
http://dx.doi.org/10.1016/j.neuropharm.2012.06.048

[183]   Gong, B., et al. (2004) Persistent Improvement in Synaptic and Cognitive Functions in an Alzheimer Mouse Model after Rolipram Treatment. Journal of Clinical Investigation, 114, 1624-1634.
http://dx.doi.org/10.1172/JCI22831

 
 
Top