title: Phosphodiesterase 7 inhibitor reduced cognitive impairment and pathological hallmarks in a mouse model of Alzheimer's disease.
abstract: Elevated levels of amyloid beta (Aβ) peptide, hyperphosphorylation of tau protein, and inflammation are pathological hallmarks in Alzheimer's disease (AD). Phosphodiesterase 7 (PDE7) regulates the inflammatory response through the cyclic adenosine monophosphate signaling cascade, and thus plays a central role in AD. The aim of this study was to evaluate the efficacy of an inhibitor of PDE7, named S14, in a mouse model of AD. We report that APP/Ps1 mice treated daily for 4 weeks with S14 show: (1) significant attenuation in behavioral impairment; (2) decreased brain Aβ deposition; (3) enhanced astrocyte-mediated Aβ degradation; and (4) decreased tau phosphorylation. These effects are mediated via the cyclic adenosine monophosphate/cyclic adenosine monophosphate response element-binding protein signaling pathway, and inactivation of glycogen synthase kinase (GSK)3. Our data support the use of PDE7 inhibitors, and specifically S14, as effective therapeutic agents for the prevention and treatment of AD.
authors.affiliation: Neuroscience Group, Instituto de Investigacion Hospital 12 de Octubre (i+12), Madrid, Spain.
authors.forename: Rocio
authors.initials: R
authors.lastname: Perez-Gonzalez
authors.forename: Consuelo
authors.initials: C
authors.lastname: Pascual
authors.forename: Desiree
authors.initials: D
authors.lastname: Antequera
authors.forename: Marta
authors.initials: M
authors.lastname: Bolos
authors.forename: Miriam
authors.initials: M
authors.lastname: Redondo
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Perez
authors.forename: Virginia
authors.initials: V
authors.lastname: Pérez-Grijalba
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Krzyzanowska
authors.forename: Manuel
authors.initials: M
authors.lastname: Sarasa
authors.forename: Carmen
authors.initials: C
authors.lastname: Gil
authors.forename: Isidro
authors.initials: I
authors.lastname: Ferrer
authors.forename: Ana
authors.initials: A
authors.lastname: Martinez
authors.forename: Eva
authors.initials: E
authors.lastname: Carro
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000209:etiology / Q000473:pathology / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001519:Behavior / Q000187:drug effects; D002478:Cells, Cultured; D003071:Cognition / Q000187:drug effects; D000242:Cyclic AMP / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000037:antagonists & inhibitors* / Q000502:physiology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D011799:Quinazolines; D016875:tau Proteins; D000242:Cyclic AMP; D038362:Glycogen Synthase Kinase 3; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7