title: Current Research Therapeutic Strategies for Alzheimer's Disease Treatment.
abstract: Alzheimer's disease (AD) currently presents one of the biggest healthcare issues in the developed countries. There is no effective treatment capable of slowing down disease progression. In recent years the main focus of research on novel pharmacotherapies was based on the amyloidogenic hypothesis of AD, which posits that the beta amyloid (Aβ) peptide is chiefly responsible for cognitive impairment and neuronal death. The goal of such treatments is (a) to reduce Aβ production through the inhibition of β and γ secretase enzymes and (b) to promote dissolution of existing cerebral Aβ plaques. However, this approach has proven to be only modestly effective. Recent studies suggest an alternative strategy centred on the inhibition of the downstream Aβ signalling, particularly at the synapse. Aβ oligomers may cause aberrant N-methyl-D-aspartate receptor (NMDAR) activation postsynaptically by forming complexes with the cell-surface prion protein (PrPC). PrPC is enriched at the neuronal postsynaptic density, where it interacts with Fyn tyrosine kinase. Fyn activation occurs when Aβ is bound to PrPC-Fyn complex. Fyn causes tyrosine phosphorylation of the NR2B subunit of metabotropic glutamate receptor 5 (mGluR5). Fyn kinase blockers masitinib and saracatinib have proven to be efficacious in treating AD symptoms in experimental mouse models of the disease.
authors.affiliation: Unitat de Bioquímica, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, C./St. Llorenç 21, Tarragona, 43201 Reus, Spain; Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Folch
authors.affiliation: Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Madrid, Spain; Unitat de Farmacologia i Farmacognòsia Facultat de Farmàcia, Institut de Biomedicina (IBUB), Universitat de Barcelona, 08028 Barcelona, Spain.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Petrov
authors.affiliation: Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Madrid, Spain; Unitat de Farmacologia i Farmacognòsia Facultat de Farmàcia, Institut de Biomedicina (IBUB), Universitat de Barcelona, 08028 Barcelona, Spain.
authors.forename: Miren
authors.initials: M
authors.lastname: Ettcheto
authors.affiliation: Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Madrid, Spain; Unitat de Farmacologia i Farmacognòsia Facultat de Farmàcia, Institut de Biomedicina (IBUB), Universitat de Barcelona, 08028 Barcelona, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Abad
authors.affiliation: Department of Physical Chemistry, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Sánchez-López
authors.affiliation: Department of Physical Chemistry, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain.
authors.forename: M Luisa
authors.initials: ML
authors.lastname: García
authors.affiliation: Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, 3460000 Talca, Chile.
authors.forename: Jordi
authors.initials: J
authors.lastname: Olloquequi
authors.affiliation: Departamento de Biología Celular y Molecular, C.U.C.B.A., Universidad de Guadalajara and División de Neurociencias, Sierra Mojada 800, Col. Independencia, 44340 Guadalajara, JAL, Mexico; Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social (IMSS), 44340 Guadalajara, JAL, Mexico.
authors.forename: Carlos
authors.initials: C
authors.lastname: Beas-Zarate
authors.affiliation: Departament de Biologia Cel.lular, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain.
authors.forename: Carme
authors.initials: C
authors.lastname: Auladell
authors.affiliation: Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Madrid, Spain; Unitat de Farmacologia i Farmacognòsia Facultat de Farmàcia, Institut de Biomedicina (IBUB), Universitat de Barcelona, 08028 Barcelona, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Camins
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001549:Benzamides; D052117:Benzodioxoles / Q000008:administration & dosage / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism; D010880:Piperidines; D018621:PrPC Proteins / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D051076:Proto-Oncogene Proteins c-fyn / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines; D011799:Quinazolines / Q000008:administration & dosage / Q000627:therapeutic use; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D013844:Thiazoles / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D016229:Amyloid beta-Peptides; D001549:Benzamides; D052117:Benzodioxoles; C578935:GRM5 protein, human; D010880:Piperidines; D018621:PrPC Proteins; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011799:Quinazolines; D064529:Receptor, Metabotropic Glutamate 5; D016194:Receptors, N-Methyl-D-Aspartate; D011985:Receptors, Serotonin; D013844:Thiazoles; C097216:serotonin 6 receptor; C515233:saracatinib; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn; C526575:masitinib