Development of Precision Small-Molecule Proneurotrophic Therapies for Neurodegenerative Diseases

Aboulkassim, 2011, Ligand-dependent TrkA activity in brain differentially affects spatial learning and long-term memory, Molecular Pharmacology, 80, 498, 10.1124/mol.111.071332 Albert, 2007, Shaping specificity in signaling networks, Nature Genetics, 39, 286, 10.1038/ng0307-286 Al-Shawi, 2008, Neurotoxic and neurotrophic roles of proNGF and the receptor sortilin in the adult and ageing nervous system, The European Journal of Neuroscience, 27, 2103, 10.1111/j.1460-9568.2008.06152.x Anderson, 2000, Selective serotonin reuptake inhibitors versus tricyclic antidepressants: A meta-analysis of efficacy and tolerability, Journal of Affective Disorders, 58, 19, 10.1016/S0165-0327(99)00092-0 Apfel, 2000, Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy: A randomized controlled trial. rhNGF Clinical Investigator Group, JAMA, 284, 2215, 10.1001/jama.284.17.2215 Appert-Collin, 2005, MAPK activation via 5-hydroxytryptamine 1A receptor is involved in the neuroprotective effects of xaliproden, International Journal of Immunopathology and Pharmacology, 18, 21, 10.1177/039463200501800104 Arrieta, 2005, Retinoic acid increases tissue and plasma contents of nerve growth factor and prevents neuropathy in diabetic mice, European Journal of Clinical Investigation, 35, 201, 10.1111/j.1365-2362.2005.01467.x Baptiste, 2006, Pharmacological approaches to repair the injured spinal cord, Journal of Neurotrauma, 23, 318, 10.1089/neu.2006.23.318 Barde, 1982, Purification of a new neurotrophic factor from mammalian brain, The EMBO Journal, 1, 549, 10.1002/j.1460-2075.1982.tb01207.x Barnham, 2003, Neurotoxic, redox-competent Alzheimer's beta-amyloid is released from lipid membrane by methionine oxidation, The Journal of Biological Chemistry, 278, 42959, 10.1074/jbc.M305494200 Bliss, 1993, A synaptic model of memory: Long-term potentiation in the hippocampus, Nature, 361, 31, 10.1038/361031a0 Boissiere, 1997, Decreased TrkA gene expression in cholinergic neurons of the striatum and basal forebrain of patients with Alzheimer's disease, Experimental Neurology, 145, 245, 10.1006/exnr.1997.6443 Bonaccorso, 2015, The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with increased body mass index and insulin resistance measures in bipolar disorder and schizophrenia, Bipolar Disorders, 17, 528, 10.1111/bdi.12294 Boulanger, 1999, Presynaptic depolarization facilitates neurotrophin-induced synaptic potentiation, Nature Neuroscience, 2, 346, 10.1038/7258 Bova, 2000, Delayed transient neurologic toxicity due to tacrolimus: CT and MRI, Neuroradiology, 42, 666, 10.1007/s002340000298 Bradshaw, 1994, Nerve growth factor: Structure/function relationships, Protein Science, 3, 1901, 10.1002/pro.5560031102 Brito, 2014, Neurotrophin receptor p75(NTR) mediates Huntington's disease-associated synaptic and memory dysfunction, The Journal of Clinical Investigation, 124, 4411, 10.1172/JCI74809 Bruno, 2006, Activity-dependent release of precursor nerve growth factor, conversion to mature nerve growth factor, and its degradation by a protease cascade, Proceedings of the National Academy of Sciences of the United States of America, 103, 6735, 10.1073/pnas.0510645103 Budni, 2015, The involvement of BDNF, NGF and GDNF in aging and Alzheimer's disease, Aging and Disease, 6, 331, 10.14336/AD.2015.0825 Cai, 2012, Metabolic dysfunction in Alzheimer's disease and related neurodegenerative disorders, Current Alzheimer Research, 9, 5, 10.2174/156720512799015064 Calissano, 2010, Nerve growth factor as a paradigm of neurotrophins related to Alzheimer's disease, Developmental Neurobiology, 70, 372 Campion, 1995, Mutations of the presenilin I gene in families with early-onset Alzheimer's disease, Human Molecular Genetics, 4, 2373, 10.1093/hmg/4.12.2373 Capsoni, 2006, On the molecular basis linking Nerve Growth Factor (NGF) to Alzheimer's disease, Cellular and Molecular Neurobiology, 26, 619 Capsoni, 2010, Dissecting the involvement of tropomyosin-related kinase A and p75 neurotrophin receptor signaling in NGF deficit-induced neurodegeneration, Proceedings of the National Academy of Sciences of the United States of America, 107, 12299, 10.1073/pnas.1007181107 Casaccia-Bonnefil, 1996, Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75, Nature, 383, 716, 10.1038/383716a0 Castren, 2004, Neurotrophic effects of antidepressant drugs, Current Opinion in Pharmacology, 4, 58, 10.1016/j.coph.2003.10.004 Chadwick, 2008, Targeting TNF-alpha receptors for neurotherapeutics, Trends in Neurosciences, 31, 504, 10.1016/j.tins.2008.07.005 Chadwick, 2011, Amitriptyline-mediated cognitive enhancement in aged 3xTg Alzheimer's disease mice is associated with neurogenesis and neurotrophic activity, PLoS One, 6, e21660, 10.1371/journal.pone.0021660 Chao, 2003, Neurotrophins and their receptors: A convergence point for many signalling pathways, Nature Reviews. Neuroscience, 4, 299, 10.1038/nrn1078 Chapman, 1995, Familial Alzheimer's disease associated with S182 codon 286 mutation, Lancet, 346, 1040, 10.1016/S0140-6736(95)91723-3 Charalampopoulos, 2012, Genetic dissection of neurotrophin signaling through the p75 neurotrophin receptor, Cell Reports, 2, 1563, 10.1016/j.celrep.2012.11.009 Chartier-Harlin, 1991, Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene, Nature, 353, 844, 10.1038/353844a0 Chen, 1997, Disruption of a single allele of the nerve growth factor gene results in atrophy of basal forebrain cholinergic neurons and memory deficits, The Journal of Neuroscience, 17, 7288, 10.1523/JNEUROSCI.17-19-07288.1997 Chen, 2010, Microarray profile of brain aging-related genes in the frontal cortex of SAMP8, Journal of Molecular Neuroscience, 41, 12, 10.1007/s12031-009-9215-6 Chen, 2005, Sortilin controls intracellular sorting of brain-derived neurotrophic factor to the regulated secretory pathway, The Journal of Neuroscience, 25, 6156, 10.1523/JNEUROSCI.1017-05.2005 Chung, 1994, PDGF- and insulin-dependent pp70S6k activation mediated by phosphatidylinositol-3-OH kinase, Nature, 370, 71, 10.1038/370071a0 Clewes, 2008, Human ProNGF: Biological effects and binding profiles at TrkA, P75NTR and sortilin, Journal of Neurochemistry, 107, 1124 Conner, 1997, Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: Evidence for anterograde axonal transport, The Journal of Neuroscience, 17, 2295, 10.1523/JNEUROSCI.17-07-02295.1997 Corbit, 1999, Protein kinase Cdelta mediates neurogenic but not mitogenic activation of mitogen-activated protein kinase in neuronal cells, Molecular and Cellular Biology, 19, 4209, 10.1128/MCB.19.6.4209 Cowansage, 2010, Brain-derived neurotrophic factor: A dynamic gatekeeper of neural plasticity, Current Molecular Pharmacology, 3, 12, 10.2174/1874467211003010012 Crutcher, 1993, Detection of NGF-like activity in human brain tissue: Increased levels in Alzheimer's disease, The Journal of Neuroscience, 13, 2540, 10.1523/JNEUROSCI.13-06-02540.1993 Cruts, 1995, Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3, Human Molecular Genetics, 4, 2363, 10.1093/hmg/4.12.2363 Cuello, 2010, Cholinergic involvement in Alzheimer's disease. A link with NGF maturation and degradation, Journal of Molecular Neuroscience, 40, 230, 10.1007/s12031-009-9238-z Dawbarn, 2003, Neurotrophins and neurodegeneration, Neuropathology and Applied Neurobiology, 29, 211, 10.1046/j.1365-2990.2003.00487.x Dawbarn, 2006, NGF receptor TrkAd5: Therapeutic agent and drug design target, Biochemical Society Transactions, 34, 587, 10.1042/BST0340587 Dechant, 2002, The neurotrophin receptor p75(NTR): Novel functions and implications for diseases of the nervous system, Nature Neuroscience, 5, 1131, 10.1038/nn1102-1131 del Peso, 1997, Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt, Science, 278, 687, 10.1126/science.278.5338.687 Devi, 2015, TrkB reduction exacerbates Alzheimer's disease-like signaling aberrations and memory deficits without affecting beta-amyloidosis in 5XFAD mice, Translational Psychiatry, 5, e562, 10.1038/tp.2015.55 Dicou, 2003, Positive allosteric modulators of AMPA receptors are neuroprotective against lesions induced by an NMDA agonist in neonatal mouse brain, Brain Research, 970, 221, 10.1016/S0006-8993(03)02357-6 Dohlman, 2015, Thematic minireview series: New directions in G protein-coupled receptor pharmacology, The Journal of Biological Chemistry, 290, 19469, 10.1074/jbc.R115.675728 Dougherty, 1999, p75NTR immunoreactivity in the rat dentate gyrus is mostly within presynaptic profiles but is also found in some astrocytic and postsynaptic profiles, The Journal of Comparative Neurology, 407, 77, 10.1002/(SICI)1096-9861(19990428)407:1<77::AID-CNE6>3.0.CO;2-S Dudek, 1997, Regulation of neuronal survival by the serine-threonine protein kinase Akt, Science, 275, 661, 10.1126/science.275.5300.661 Dutta, 2006, Current insights into the regulation of programmed cell death by NF-kappaB, Oncogene, 25, 6800, 10.1038/sj.onc.1209938 Egan, 2003, The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function, Cell, 112, 257, 10.1016/S0092-8674(03)00035-7 Eguchi, 1998, Calcium-dependent epidermal growth factor receptor transactivation mediates the angiotensin II-induced mitogen-activated protein kinase activation in vascular smooth muscle cells, Journal of Biological Chemistry, 273, 8890, 10.1074/jbc.273.15.8890 Elliott, 2005, Brain-derived neurotrophic factor induces a rapid dephosphorylation of tau protein through a PI-3 Kinase signalling mechanism, The European Journal of Neuroscience, 22, 1081, 10.1111/j.1460-9568.2005.04290.x Engert, 1999, Dendritic spine changes associated with hippocampal long-term synaptic plasticity, Nature, 399, 66, 10.1038/19978 Ernfors, 1994, Lack of neurotrophin-3 leads to deficiencies in the peripheral nervous system and loss of limb proprioceptive afferents, Cell, 77, 503, 10.1016/0092-8674(94)90213-5 Evans, 2011, Neuronal brain-derived neurotrophic factor is synthesized in excess, with levels regulated by sortilin-mediated trafficking and lysosomal degradation, The Journal of Biological Chemistry, 286, 29556, 10.1074/jbc.M111.219675 Figurov, 1996, Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus, Nature, 381, 706, 10.1038/381706a0 Gentry, 2004, A functional interaction between the p75 neurotrophin receptor interacting factors, TRAF6 and NRIF, The Journal of Biological Chemistry, 279, 16646, 10.1074/jbc.M309209200 Gerlai, 2001, Alzheimer's disease: Beta-amyloid hypothesis strengthened!, Trends in Neurosciences, 24, 199, 10.1016/S0166-2236(00)01799-9 Gille, 1992, Phosphorylation of transcription factor p62TCF by MAP kinase stimulates ternary complex formation at c-fos promoter, Nature, 358, 414, 10.1038/358414a0 Goate, 1991, Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease, Nature, 349, 704, 10.1038/349704a0 Golden, 2010, Circulating brain-derived neurotrophic factor and indices of metabolic and cardiovascular health: Data from the Baltimore Longitudinal Study of Aging, PLoS One, 5, e10099, 10.1371/journal.pone.0010099 Gomez-Palacio-Schjetnan, 2013, Neurotrophins and synaptic plasticity, Current Topics in Behavioral Neurosciences, 15, 117, 10.1007/7854_2012_231 Gotz, 1994, Neurotrophin-6 is a new member of the nerve growth factor family, Nature, 372, 266, 10.1038/372266a0 Haase, 1997, Gene therapy of murine motor neuron disease using adenoviral vectors for neurotrophic factors, Nature Medicine, 3, 429, 10.1038/nm0497-429 Halban, 1994, Sorting and processing of secretory proteins, The Biochemical Journal, 299, 1, 10.1042/bj2990001 Harandi, 2014, Analysis of neurotrophic factors in limb and extraocular muscles of mouse model of amyotrophic lateral sclerosis, PLoS One, 9, e109833, 10.1371/journal.pone.0109833 Hardy, 2002, The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics, Science, 297, 353, 10.1126/science.1072994 Heightman, 2005, 8-Piperazinyl-2,3-dihydropyrrolo[3,2-g]isoquinolines: Potent, selective, orally bioavailable 5-HT1 receptor ligands, Bioorganic & Medicinal Chemistry Letters, 15, 4370, 10.1016/j.bmcl.2005.06.042 Hellweg, 1998, NGF content in the cerebral cortex of non-demented patients with amyloid-plaques and in symptomatic Alzheimer's disease, International Journal of Developmental Neuroscience, 16, 787, 10.1016/S0736-5748(98)00088-4 Hempstead, 2002, The many faces of p75NTR, Current Opinion in Neurobiology, 12, 260, 10.1016/S0959-4388(02)00321-5 Herskowitz, 2013, Pharmacologic inhibition of ROCK2 suppresses amyloid-beta production in an Alzheimer's disease mouse model, The Journal of Neuroscience, 33, 19086, 10.1523/JNEUROSCI.2508-13.2013 Hill, 1995, Transcriptional regulation by extracellular signals: Mechanisms and specificity, Cell, 80, 199, 10.1016/0092-8674(95)90403-4 Hock, 2000, Region-specific neurotrophin imbalances in Alzheimer disease: Decreased levels of brain-derived neurotrophic factor and increased levels of nerve growth factor in hippocampus and cortical areas, Archives of Neurology, 57, 846, 10.1001/archneur.57.6.846 Holgado-Madruga, 1997, Grb2-associated binder-1 mediates phosphatidylinositol 3-kinase activation and the promotion of cell survival by nerve growth factor, Proceedings of the National Academy of Sciences of the United States of America, 94, 12419, 10.1073/pnas.94.23.12419 Hu, 2002, Increased p75(NTR) expression in hippocampal neurons containing hyperphosphorylated tau in Alzheimer patients, Experimental Neurology, 178, 104, 10.1006/exnr.2002.8018 Huang, 2003, Trk receptors: Roles in neuronal signal transduction, Annual Review of Biochemistry, 72, 609, 10.1146/annurev.biochem.72.121801.161629 Ibanez, 1995, Neurotrophic factors: From structure–function studies to designing effective therapeutics, Trends in Biotechnology, 13, 217, 10.1016/S0167-7799(00)88949-0 Ichim, 2012, Neurotrophins and cell death, Experimental Cell Research, 318, 1221, 10.1016/j.yexcr.2012.03.006 Inoue, 2000, Tumor necrosis factor receptor-associated factor (TRAF) family: Adapter proteins that mediate cytokine signaling, Experimental Cell Research, 254, 14, 10.1006/excr.1999.4733 Ip, 1992, Mammalian neurotrophin-4: Structure, chromosomal localization, tissue distribution, and receptor specificity, Proceedings of the National Academy of Sciences of the United States of America, 89, 3060, 10.1073/pnas.89.7.3060 Jang, 2010, Deoxygedunin, a natural product with potent neurotrophic activity in mice, PLoS One, 5, e11528, 10.1371/journal.pone.0011528 Jang, 2009, Amitriptyline is a TrkA and TrkB receptor agonist that promotes TrkA/TrkB heterodimerization and has potent neurotrophic activity, Chemistry & Biology, 16, 644, 10.1016/j.chembiol.2009.05.010 Jang, 2010, A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone, Proceedings of the National Academy of Sciences of the United States of America, 107, 2687, 10.1073/pnas.0913572107 Jang, 2007, Gambogic amide, a selective agonist for TrkA receptor that possesses robust neurotrophic activity, prevents neuronal cell death, Proceedings of the National Academy of Sciences of the United States of America, 104, 16329, 10.1073/pnas.0706662104 Janssens, 2014, Systems-level G protein-coupled receptor therapy across a neurodegenerative continuum by the GLP-1 receptor system, Frontiers in Endocrinology (Lausanne), 5, 142 Jean-Alphonse, 2014, Spatially restricted G protein-coupled receptor activity via divergent endocytic compartments, The Journal of Biological Chemistry, 289, 3960, 10.1074/jbc.M113.526350 Jovanovic, 2000, Synapsins as mediators of BDNF-enhanced neurotransmitter release, Nature Neuroscience, 3, 323, 10.1038/73888 Jung, 2010, Control of TrkA-induced cell death by JNK activation and differential expression of TrkA upon DNA damage, Molecules and Cells, 30, 121, 10.1007/s10059-010-0096-x Kang, 1997, Neurotrophins and time: Different roles for TrkB signaling in hippocampal long-term potentiation, Neuron, 19, 653, 10.1016/S0896-6273(00)80378-5 Kauffmann-Zeh, 1997, Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB, Nature, 385, 544, 10.1038/385544a0 Kelly, 2000, Deficits in nerve growth factor release and tyrosine receptor kinase phosphorylation are associated with age-related impairment in long-term potentiation in the dentate gyrus, Neuroscience, 95, 359, 10.1016/S0306-4522(99)00460-1 Kichev, 2009, Cell death and learning impairment in mice caused by in vitro modified pro-NGF can be related to its increased oxidative modifications in Alzheimer disease, The American Journal of Pathology, 175, 2574, 10.2353/ajpath.2009.090018 Kim, 2006, Abeta star: A light onto synaptic dysfunction?, Nature Medicine, 12, 760, 10.1038/nm0706-760 Kimura, 2006, Amyloid beta up-regulates brain-derived neurotrophic factor production from astrocytes: Rescue from amyloid beta-related neuritic degeneration, Journal of Neuroscience Research, 84, 782, 10.1002/jnr.20984 Klein, 1991, The trk proto-oncogene encodes a receptor for nerve growth factor, Cell, 65, 189, 10.1016/0092-8674(91)90419-Y Klein, 1992, The trkB tyrosine protein kinase is a receptor for neurotrophin-4, Neuron, 8, 947, 10.1016/0896-6273(92)90209-V Klein, 1991, The trkB tyrosine protein kinase is a receptor for brain-derived neurotrophic factor and neurotrophin-3, Cell, 66, 395, 10.1016/0092-8674(91)90628-C Knowles, 2013, Small molecule p75NTR ligand prevents cognitive deficits and neurite degeneration in an Alzheimer's mouse model, Neurobiology of Aging, 34, 2052, 10.1016/j.neurobiolaging.2013.02.015 Korsching, 1985, Levels of nerve growth factor and its mRNA in the central nervous system of the rat correlate with cholinergic innervation, The EMBO Journal, 4, 1389, 10.1002/j.1460-2075.1985.tb03791.x Lamballe, 1991, trkC, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3, Cell, 66, 967, 10.1016/0092-8674(91)90442-2 Lange-Carter, 1994, Ras-dependent growth factor regulation of MEK kinase in PC12 cells, Science, 265, 1458, 10.1126/science.8073291 Leal, 2014, BDNF-induced local protein synthesis and synaptic plasticity, Neuropharmacology, 76, 639, 10.1016/j.neuropharm.2013.04.005 Lee, 2001, Activation of Trk neurotrophin receptors in the absence of neurotrophins, Proceedings of the National Academy of Sciences of the United States of America, 98, 3555, 10.1073/pnas.061020198 Lee, 2002, Activation of Trk neurotrophin receptor signaling by pituitary adenylate cyclase-activating polypeptides, Journal of Biological Chemistry, 277, 9096, 10.1074/jbc.M107421200 Lee, 2001, Regulation of cell survival by secreted proneurotrophins, Science, 294, 1945, 10.1126/science.1065057 Lemmon, 2010, Cell signaling by receptor tyrosine kinases, Cell, 141, 1117, 10.1016/j.cell.2010.06.011 Lessmann, 2009, Mechanisms, locations, and kinetics of synaptic BDNF secretion: An update, Neuroscience Research, 65, 11, 10.1016/j.neures.2009.06.004 Lessmann, 2003, Neurotrophin secretion: Current facts and future prospects, Progress in Neurobiology, 69, 341, 10.1016/S0301-0082(03)00019-4 Levi-Montalcini, 1987, The nerve growth factor 35 years later, Science, 237, 1154, 10.1126/science.3306916 Liepinsh, 1997, NMR structure of the death domain of the p75 neurotrophin receptor, The EMBO Journal, 16, 4999, 10.1093/emboj/16.16.4999 Lin, 2007, Neuroprotection by small molecule activators of the nerve growth factor receptor, The Journal of Pharmacology and Experimental Therapeutics, 322, 59, 10.1124/jpet.106.118034 Liu, 2004, Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity, Science, 304, 1021, 10.1126/science.1096615 Longo, 2013, Small-molecule modulation of neurotrophin receptors: A strategy for the treatment of neurological disease, Nature Reviews. Drug Discovery, 12, 507, 10.1038/nrd4024 Longo, 2007, Small molecule neurotrophin receptor ligands: Novel strategies for targeting Alzheimer's disease mechanisms, Current Alzheimer Research, 4, 503, 10.2174/156720507783018316 Lonze, 2002, Apoptosis, axonal growth defects, and degeneration of peripheral neurons in mice lacking CREB, Neuron, 34, 371, 10.1016/S0896-6273(02)00686-4 Lu, 2005, The yin and yang of neurotrophin action, Nature Reviews. Neuroscience, 6, 603, 10.1038/nrn1726 Lu, 2005, Identification of polyclonal and monoclonal antibodies against tissue plasminogen activator in the antiphospholipid syndrome, Arthritis and Rheumatism, 52, 4018, 10.1002/art.21485 Lu, 2013, TROY interacts with Rho guanine nucleotide dissociation inhibitor alpha (RhoGDIalpha) to mediate Nogo-induced inhibition of neurite outgrowth, The Journal of Biological Chemistry, 288, 34276, 10.1074/jbc.M113.519744 Luttrell, 2015, Fulfilling the promise of “biased” G protein-coupled receptor agonism, Molecular Pharmacology, 88, 579, 10.1124/mol.115.099630 Malberg, 2005, Antidepressant action: To the nucleus and beyond, Trends in Pharmacological Sciences, 26, 631, 10.1016/j.tips.2005.10.005 Maletic-Savatic, 1999, Rapid dendritic morphogenesis in CA1 hippocampal dendrites induced by synaptic activity, Science, 283, 1923, 10.1126/science.283.5409.1923 Marinissen, 1999, A network of mitogen-activated protein kinases links G protein-coupled receptors to the c-jun promoter: A role for c-Jun NH2-terminal kinase, p38s, and extracellular signal-regulated kinase 5, Molecular and Cellular Biology, 19, 4289, 10.1128/MCB.19.6.4289 Martin, 2009, Growth factor signals in neural cells: Coherent patterns of interaction control multiple levels of molecular and phenotypic responses, The Journal of Biological Chemistry, 284, 2493, 10.1074/jbc.M804545200 Martin, 2013, Plurigon: Three dimensional visualization and classification of high-dimensionality data, Frontiers in Physiology, 4, 190, 10.3389/fphys.2013.00190 Masoudi, 2009, Biological activity of nerve growth factor precursor is dependent upon relative levels of its receptors, The Journal of Biological Chemistry, 284, 18424, 10.1074/jbc.M109.007104 Massa, 2006, Small, nonpeptide p75NTR ligands induce survival signaling and inhibit proNGF-induced death, The Journal of Neuroscience, 26, 5288, 10.1523/JNEUROSCI.3547-05.2006 Massa, 2010, Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents, The Journal of Clinical Investigation, 120, 1774, 10.1172/JCI41356 Massey, 2004, Differential roles of NR2A and NR2B-containing NMDA receptors in cortical long-term potentiation and long-term depression, The Journal of Neuroscience, 24, 7821, 10.1523/JNEUROSCI.1697-04.2004 Matsumoto, 2001, Brain-derived neurotrophic factor enhances depolarization-evoked glutamate release in cultured cortical neurons, Journal of Neurochemistry, 79, 522, 10.1046/j.1471-4159.2001.00591.x Mattson, 2004, Pathways towards and away from Alzheimer's disease, Nature, 430, 631, 10.1038/nature02621 Maudsley, 2012, G protein-coupled receptor biased agonism: Development towards future selective therapeutics, Mini Reviews in Medicinal Chemistry, 12, 803, 10.2174/138955712800959161 Maudsley, 2011, To be or not to be—Obese, Endocrinology, 152, 3592, 10.1210/en.2011-1615 Maudsley, 2015, Delineation of a conserved arrestin-biased signaling repertoire in vivo, Molecular Pharmacology, 87, 706, 10.1124/mol.114.095224 Maudsley, 2005, The origins of diversity and specificity in g protein-coupled receptor signaling, The Journal of Pharmacology and Experimental Therapeutics, 314, 485, 10.1124/jpet.105.083121 Maudsley, 2007, G protein-coupled receptor signaling complexity in neuronal tissue: Implications for novel therapeutics, Current Alzheimer Research, 4, 3, 10.2174/156720507779939850 Maudsley, 2006, Protein twists and turns in Alzheimer disease, Nature Medicine, 12, 392, 10.1038/nm0406-392 Maudsley, 2012, Functional signaling biases in G protein-coupled receptors: Game Theory and receptor dynamics, Mini Reviews in Medicinal Chemistry, 12, 831, 10.2174/138955712800959071 Maudsley, 2000, The beta(2)-adrenergic receptor mediates extracellular signal-regulated kinase activation via assembly of a multi-receptor complex with the epidermal growth factor receptor, Journal of Biological Chemistry, 275, 9572, 10.1074/jbc.275.13.9572 McAllister, 1996, Neurotrophin regulation of cortical dendritic growth requires activity, Neuron, 17, 1057, 10.1016/S0896-6273(00)80239-1 McClean, 2007, Cross-talk and decision making in MAP kinase pathways, Nature Genetics, 39, 409, 10.1038/ng1957 McKhann, 2011, The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's disease, Alzheimers Dement, 7, 263, 10.1016/j.jalz.2011.03.005 McMahon, 1994, Expression and coexpression of Trk receptors in subpopulations of adult primary sensory neurons projecting to identified peripheral targets, Neuron, 12, 1161, 10.1016/0896-6273(94)90323-9 Mey, 2004, Retinoic acid signaling in the nervous system of adult vertebrates, The Neuroscientist, 10, 409, 10.1177/1073858404263520 Meyer-Franke, 1995, Characterization of the signaling interactions that promote the survival and growth of developing retinal ganglion cells in culture, Neuron, 15, 805, 10.1016/0896-6273(95)90172-8 Miller, 2000, Neurotrophin receptors in the somatosensory cortex of the mature rat: Co-localization of p75, trk, isoforms and c-neu, Brain Research, 852, 355, 10.1016/S0006-8993(99)02176-9 Minichiello, 2002, Mechanism of TrkB-mediated hippocampal long-term potentiation, Neuron, 36, 121, 10.1016/S0896-6273(02)00942-X Mizui, 2015, BDNF pro-peptide actions facilitate hippocampal LTD and are altered by the common BDNF polymorphism Val66Met, Proceedings of the National Academy of Sciences of the United States of America, 112, E3067, 10.1073/pnas.1422336112 Morris, 1998, Sortilin is the major 110-kDa protein in GLUT4 vesicles from adipocytes, The Journal of Biological Chemistry, 273, 3582, 10.1074/jbc.273.6.3582 Mou, 2015, Human obesity associated with an intronic SNP in the brain-derived neurotrophic factor locus, Cell Reports, 13, 1073, 10.1016/j.celrep.2015.09.065 Mueller, 2005, Rho kinase, a promising drug target for neurological disorders, Nature Reviews. Drug Discovery, 4, 387, 10.1038/nrd1719 Mufson, 1995, Nerve growth factor in Alzheimer's disease: Defective retrograde transport to nucleus basalis, Neuroreport, 6, 1063, 10.1097/00001756-199505090-00028 Mufson, 1992, Cortical neurons express nerve growth factor receptors in advanced age and Alzheimer disease, Proceedings of the National Academy of Sciences of the United States of America, 89, 569, 10.1073/pnas.89.2.569 Mufson, 1999, Distribution and retrograde transport of trophic factors in the central nervous system: Functional implications for the treatment of neurodegenerative diseases, Progress in Neurobiology, 57, 451, 10.1016/S0301-0082(98)00059-8 Mukai, 2000, NADE, a p75NTR-associated cell death executor, is involved in signal transduction mediated by the common neurotrophin receptor p75NTR, The Journal of Biological Chemistry, 275, 17566, 10.1074/jbc.C000140200 Mullan, 1992, A locus for familial early-onset Alzheimer's disease on the long arm of chromosome 14, proximal to the alpha 1-antichymotrypsin gene, Nature Genetics, 2, 340, 10.1038/ng1292-340 Murer, 2001, Brain-derived neurotrophic factor in the control human brain, and in Alzheimer's disease and Parkinson's disease, Progress in Neurobiology, 63, 71, 10.1016/S0301-0082(00)00014-9 Narisawa-Saito, 1996, Regional specificity of alterations in NGF, BDNF and NT-3 levels in Alzheimer's disease, Neuroreport, 7, 2925, 10.1097/00001756-199611250-00024 Nielsen, 2001, The sortilin cytoplasmic tail conveys Golgi-endosome transport and binds the VHS domain of the GGA2 sorting protein, The EMBO Journal, 20, 2180, 10.1093/emboj/20.9.2180 Nimnual, 1998, Coupling of Ras and Rac guanosine triphosphatases through the Ras exchanger SoS, Science, 279, 560, 10.1126/science.279.5350.560 Nykjaer, 2004, Sortilin is essential for proNGF-induced neuronal cell death, Nature, 427, 843, 10.1038/nature02319 Nykjaer, 2012, Sortilin: A receptor to regulate neuronal viability and function, Trends in Neurosciences, 35, 261, 10.1016/j.tins.2012.01.003 Nykjaer, 2005, p75NTR—Live or let die, Current Opinion in Neurobiology, 15, 49, 10.1016/j.conb.2005.01.004 O'Neill, 2005, LY503430: Pharmacology, pharmacokinetics, and effects in rodent models of Parkinson's disease, CNS Drug Reviews, 11, 77, 10.1111/j.1527-3458.2005.tb00037.x Pang, 2004, Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity, Science, 306, 487, 10.1126/science.1100135 Patapoutian, 2001, Trk receptors: Mediators of neurotrophin action, Current Opinion in Neurobiology, 11, 272, 10.1016/S0959-4388(00)00208-7 Patterson, 1996, Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice, Neuron, 16, 1137, 10.1016/S0896-6273(00)80140-3 Pearson, 2001, Mitogen-activated protein (MAP) kinase pathways: Regulation and physiological functions, Endocrine Reviews, 22, 153 Pedraza, 2005, Pro-NGF isolated from the human brain affected by Alzheimer's disease induces neuronal apoptosis mediated by p75NTR, The American Journal of Pathology, 166, 533, 10.1016/S0002-9440(10)62275-4 Peng, 2004, Increased proNGF levels in subjects with mild cognitive impairment and mild Alzheimer disease, Journal of Neuropathology and Experimental Neurology, 63, 641, 10.1093/jnen/63.6.641 Petratos, 2008, The beta-amyloid protein of Alzheimer's disease increases neuronal CRMP-2 phosphorylation by a Rho-GTP mechanism, Brain, 131, 90, 10.1093/brain/awm260 Pham, 2016, p75 neurotrophin receptor signaling activates sterol regulatory element-binding protein-2 in hepatocyte cells via p38 mitogen-activated protein kinase and caspase-3, The Journal of Biological Chemistry, 291, 10747, 10.1074/jbc.M116.722272 Plow, 1995, The cell biology of the plasminogen system, The FASEB Journal, 9, 939, 10.1096/fasebj.9.10.7615163 Pollack, 1999, The staurosporine-like compound L-753,000 (NB-506) potentiates the neurotrophic effects of neurotrophin-3 by acting selectively at the TrkA receptor, Molecular Pharmacology, 56, 185, 10.1124/mol.56.1.185 Poo, 2001, Neurotrophins as synaptic modulators, Nature Reviews. Neuroscience, 2, 24, 10.1038/35049004 Potkin, 2002, Brain metabolic effects of Neotrofin in patients with Alzheimer's disease, Brain Research, 951, 87, 10.1016/S0006-8993(02)03140-2 Pradines, 1995, Evidence for nerve growth factor-potentiating activities of the nonpeptidic compound SR 57746A in PC12 cells, Journal of Neurochemistry, 64, 1954, 10.1046/j.1471-4159.1995.64051954.x Rajagopal, 2004, Transactivation of Trk neurotrophin receptors by G-protein-coupled receptor ligands occurs on intracellular membranes, Journal of Neuroscience, 24, 6650, 10.1523/JNEUROSCI.0010-04.2004 Ramirez, 2002, The effects of Neotrofin on septodentate sprouting after unilateral entorhinal cortex lesions in rats, Restorative Neurology and Neuroscience, 20, 51 Rathbone, 1999, AIT-082 as a potential neuroprotective and regenerative agent in stroke and central nervous system injury, Expert Opinion on Investigational Drugs, 8, 1255, 10.1517/13543784.8.8.1255 Rathbone, 1999, Trophic effects of purines in neurons and glial cells, Progress in Neurobiology, 59, 663, 10.1016/S0301-0082(99)00017-9 Rattenholl, 2001, Pro-sequence assisted folding and disulfide bond formation of human nerve growth factor, Journal of Molecular Biology, 305, 523, 10.1006/jmbi.2000.4295 Ravni, 2006, The neurotrophic effects of PACAP in PC12 cells: Control by multiple transduction pathways, Journal of Neurochemistry, 98, 321, 10.1111/j.1471-4159.2006.03884.x Reichardt, 2006, Neurotrophin-regulated signalling pathways, Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 361, 1545, 10.1098/rstb.2006.1894 Roux, 2002, Neurotrophin signaling through the p75 neurotrophin receptor, Progress in Neurobiology, 67, 203, 10.1016/S0301-0082(02)00016-3 Roux, 2002, K252a and CEP1347 are neuroprotective compounds that inhibit mixed-lineage kinase-3 and induce activation of Akt and ERK, The Journal of Biological Chemistry, 277, 49473, 10.1074/jbc.M203428200 Sagot, 1998, Differential effects of neurotrophic factors on motoneuron retrograde labeling in a murine model of motoneuron disease, The Journal of Neuroscience, 18, 1132, 10.1523/JNEUROSCI.18-03-01132.1998 Salehi, 1996, Co-localization of high-affinity neurotrophin receptors in nucleus basalis of Meynert neurons and their differential reduction in Alzheimer's disease, Neuroscience, 75, 373, 10.1016/0306-4522(96)00273-4 Scarpi, 2012, Low molecular weight, non-peptidic agonists of TrkA receptor with NGF-mimetic activity, Cell Death & Disease, 3, e339, 10.1038/cddis.2012.80 Schecterson, 2010, Neurotrophin receptors: Old friends with new partners, Developmental Neurobiology, 70, 332 Schmid, 2012, A TrkB small molecule partial agonist rescues TrkB phosphorylation deficits and improves respiratory function in a mouse model of Rett syndrome, The Journal of Neuroscience, 32, 1803, 10.1523/JNEUROSCI.0865-11.2012 Scott, 1995, Nerve growth factor in Alzheimer's disease: Increased levels throughout the brain coupled with declines in nucleus basalis, The Journal of Neuroscience, 15, 6213, 10.1523/JNEUROSCI.15-09-06213.1995 Segal, 1996, Intracellular signaling pathways activated by neurotrophic factors, Annual Review of Neuroscience, 19, 463, 10.1146/annurev.ne.19.030196.002335 Shen, 2012, Brain-derived neurotrophic factor receptor TrkB exists as a preformed dimer in living cells, Journal of Molecular Signaling, 7, 2, 10.1186/1750-2187-7-2 Sherrington, 1995, Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease, Nature, 375, 754, 10.1038/375754a0 Shetty, 2005, Stem/progenitor cell proliferation factors FGF-2, IGF-1, and VEGF exhibit early decline during the course of aging in the hippocampus: Role of astrocytes, Glia, 51, 173, 10.1002/glia.20187 Shoji, 1992, Production of the Alzheimer amyloid beta protein by normal proteolytic processing, Science, 258, 126, 10.1126/science.1439760 Shu, 2015, Update on the role of p75NTR in neurological disorders: A novel therapeutic target, Biomedicine & Pharmacotherapy, 76, 17, 10.1016/j.biopha.2015.10.010 Siddiqui, 2012, Central role of the EGF receptor in neurometabolic aging, International Journal of Endocrinology, 2012, 739428, 10.1155/2012/739428 Skaper, 1998, Neurotrophins rescue cerebellar granule neurons from oxidative stress-mediated apoptotic death: Selective involvement of phosphatidylinositol 3-kinase and the mitogen-activated protein kinase pathway, Journal of Neurochemistry, 70, 1859, 10.1046/j.1471-4159.1998.70051859.x Skeldal, 2011, Proteolytic processing of the p75 neurotrophin receptor: A prerequisite for signalling? Neuronal life, growth and death signalling are crucially regulated by intra-membrane proteolysis and trafficking of p75(NTR), Bioessays, 33, 614, 10.1002/bies.201100036 Sobreviela, 1994, TrkA-immunoreactive profiles in the central nervous system: Colocalization with neurons containing p75 nerve growth factor receptor, choline acetyltransferase, and serotonin, The Journal of Comparative Neurology, 350, 587, 10.1002/cne.903500407 Steiner, 1997, Neurotrophic immunophilin ligands stimulate structural and functional recovery in neurodegenerative animal models, Proceedings of the National Academy of Sciences of the United States of America, 94, 2019, 10.1073/pnas.94.5.2019 Stoop, 1995, Potentiation of transmitter release by ciliary neurotrophic factor requires somatic signaling, Science, 267, 695, 10.1126/science.7839148 Stranahan, 2009, Pharmacomimetics of exercise: Novel approaches for hippocampally-targeted neuroprotective agents, Current Medicinal Chemistry, 16, 4668, 10.2174/092986709789878292 Struble, 2010, Is brain amyloid production a cause or a result of dementia of the Alzheimer's type?, Journal of Alzheimer's Disease, 22, 393, 10.3233/JAD-2010-100846 Swift, 2011, Quantification of receptor tyrosine kinase transactivation through direct dimerization and surface density measurements in single cells, Proceedings of the National Academy of Sciences of the United States of America, 108, 7016, 10.1073/pnas.1018280108 Takebayashi, 2002, Nerve growth factor-induced neurite sprouting in PC12 cells involves sigma-1 receptors: Implications for antidepressants, The Journal of Pharmacology and Experimental Therapeutics, 303, 1227, 10.1124/jpet.102.041970 Tapia-Arancibia, 2008, New insights into brain BDNF function in normal aging and Alzheimer disease, Brain Research Reviews, 59, 201, 10.1016/j.brainresrev.2008.07.007 Terracciano, 2010, Plasma BDNF concentration, Val66Met genetic variant and depression-related personality traits, Genes, Brain, and Behavior, 9, 512 Terry, 2011, Age-dependent alterations in nerve growth factor (NGF)-related proteins, sortilin, and learning and memory in rats, Physiology & Behavior, 102, 149, 10.1016/j.physbeh.2010.11.005 Thoenen, 2002, Neurotrophins: From enthusiastic expectations through sobering experiences to rational therapeutic approaches, Nature Neuroscience, 5, 1046, 10.1038/nn938 Toni, 1999, LTP promotes formation of multiple spine synapses between a single axon terminal and a dendrite, Nature, 402, 421, 10.1038/46574 Trommald, 1996, Long-term potentiation is associated with new excitatory spine synapses on rat dentate granule cells, Learning & Memory, 3, 218, 10.1101/lm.3.2-3.218 Tsai, 2003, Brain-derived neurotrophic factor: A bridge between major depression and Alzheimer's disease?, Medical Hypotheses, 61, 110, 10.1016/S0306-9877(03)00141-5 Tsirka, 1997, Clinical implications of the involvement of tPA in neuronal cell death, Journal of Molecular Medicine (Berlin, Germany), 75, 341, 10.1007/s001090050119 Tsou, 2014, Receptor tyrosine kinases, TYRO3, AXL, and MER, demonstrate distinct patterns and complex regulation of ligand-induced activation, The Journal of Biological Chemistry, 289, 25750, 10.1074/jbc.M114.569020 Vaegter, 2011, Sortilin associates with Trk receptors to enhance anterograde transport and neurotrophin signaling, Nature Neuroscience, 14, 54, 10.1038/nn.2689 Vaillant, 1999, Depolarization and neurotrophins converge on the phosphatidylinositol 3-kinase-Akt pathway to synergistically regulate neuronal survival, The Journal of Cell Biology, 146, 955, 10.1083/jcb.146.5.955 Ventriglia, 2013, Serum brain-derived neurotrophic factor levels in different neurological diseases, BioMed Research International, 2013, 901082, 10.1155/2013/901082 Vicario-Abejon, 2002, Role of neurotrophins in central synapse formation and stabilization, Nature Reviews. Neuroscience, 3, 965, 10.1038/nrn988 Voda, 2005, Neuroimmunophilin ligands improve functional recovery and increase axonal growth after spinal cord hemisection in rats, Journal of Neurotrauma, 22, 1150, 10.1089/neu.2005.22.1150 Volosin, 2006, Interaction of survival and death signaling in basal forebrain neurons: Roles of neurotrophins and proneurotrophins, The Journal of Neuroscience, 26, 7756, 10.1523/JNEUROSCI.1560-06.2006 Wang, 2009, Allosteric modulators of g protein-coupled receptors: Future therapeutics for complex physiological disorders, The Journal of Pharmacology and Experimental Therapeutics, 331, 340, 10.1124/jpet.109.156380 Wang, 2011, Neural fate decisions mediated by trans-activation and cis-inhibition in Notch signaling, Bioinformatics, 27, 3158, 10.1093/bioinformatics/btr551 Wasco, 1995, Familial Alzheimer's chromosome 14 mutations, Nature Medicine, 1, 848, 10.1038/nm0995-848a Watson, 2001, Neurotrophins use the Erk5 pathway to mediate a retrograde survival response, Nature Neuroscience, 4, 981, 10.1038/nn720 Weissmiller, 2012, Current advances in using neurotrophic factors to treat neurodegenerative disorders, Translational Neurodegeneration, 1, 14, 10.1186/2047-9158-1-14 Wellmer, 2001, A double-blind placebo-controlled clinical trial of recombinant human brain-derived neurotrophic factor (rhBDNF) in diabetic polyneuropathy, Journal of the Peripheral Nervous System, 6, 204, 10.1046/j.1529-8027.2001.01019.x Whitmarsh, 1998, Structural organization of MAP-kinase signaling modules by scaffold proteins in yeast and mammals, Trends in Biochemical Sciences, 23, 481, 10.1016/S0968-0004(98)01309-7 Wiesmann, 2001, Nerve growth factor: Structure and function, Cellular and Molecular Life Sciences, 58, 748, 10.1007/PL00000898 Williams, 2005, Overcoming the inhibitors of myelin with a novel neurotrophin strategy, The Journal of Biological Chemistry, 280, 5862, 10.1074/jbc.M411121200 Willnow, 2008, VPS10P-domain receptors—Regulators of neuronal viability and function, Nature Reviews. Neuroscience, 9, 899, 10.1038/nrn2516 Woo, 2005, Activation of p75NTR by proBDNF facilitates hippocampal long-term depression, Nature Neuroscience, 8, 1069, 10.1038/nn1510 Wood, 1992, ras mediates nerve growth factor receptor modulation of three signal-transducing protein kinases: MAP kinase, Raf-1, and RSK, Cell, 68, 1041, 10.1016/0092-8674(92)90076-O Wu, 2004, AMPA protects cultured neurons against glutamate excitotoxicity through a phosphatidylinositol 3-kinase-dependent activation in extracellular signal-regulated kinase to upregulate BDNF gene expression, Journal of Neurochemistry, 90, 807, 10.1111/j.1471-4159.2004.02526.x Yang, 2008, Small molecule, non-peptide p75 ligands inhibit Abeta-induced neurodegeneration and synaptic impairment, PLoS One, 3, e3604, 10.1371/journal.pone.0003604 Yao, 1997, Induction of neurite outgrowth in PC12 cells by gamma-lactam-related compounds via Ras-MAP kinase signaling pathway independent mechanism, Experimental Cell Research, 234, 233, 10.1006/excr.1997.3615 Ye, 1999, TRAF family proteins interact with the common neurotrophin receptor and modulate apoptosis induction, The Journal of Biological Chemistry, 274, 30202, 10.1074/jbc.274.42.30202 Yoon, 1998, Competitive signaling between TrkA and p75 nerve growth factor receptors determines cell survival, The Journal of Neuroscience, 18, 3273, 10.1523/JNEUROSCI.18-09-03273.1998 Yuan, 2003, Diversity in the mechanisms of neuronal cell death, Neuron, 40, 401, 10.1016/S0896-6273(03)00601-9 Yuen, 1996, Nerve growth factor and the neurotrophic factor hypothesis, Brain Dev, 18, 362, 10.1016/0387-7604(96)00051-4 Zhang, 2003, p75 neurotrophin receptor protects primary cultures of human neurons against extracellular amyloid beta peptide cytotoxicity, The Journal of Neuroscience, 23, 7385, 10.1523/JNEUROSCI.23-19-07385.2003 Zuccato, 2009, Brain-derived neurotrophic factor in neurodegenerative diseases, Nature Reviews. Neurology, 5, 311, 10.1038/nrneurol.2009.54