Phosphodiesterase 7 inhibitor reduced cognitive impairment and pathological hallmarks in a mouse model of Alzheimer's disease

• Published in: Neurobiology of aging 2013-09, Vol.34 (9), p.2133-2145
• Main Authors: Perez-Gonzalez, Rocio, Pascual, Consuelo, Antequera, Desiree, Bolos, Marta, Redondo, Miriam, Perez, Daniel I, Pérez-Grijalba, Virginia, Krzyzanowska, Agnieszka, Sarasa, Manuel, Gil, Carmen, Ferrer, Isidro, Martinez, Ana, Carro, Eva
• Format: Article
• Language: English
• Subjects: Aging; Alzheimer Disease - drug therapy; Alzheimer Disease - etiology; Alzheimer Disease - pathology; Alzheimer Disease - psychology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Animals; Astrocytes; Astrocytes - metabolism; Aβ degradation; Behavior - drug effects; Cells, Cultured; Cognition; Cognition - drug effects; Cyclic AMP - physiology; Cyclic AMP Response Element-Binding Protein - physiology; Cyclic Nucleotide Phosphodiesterases, Type 7 - antagonists & inhibitors; Cyclic Nucleotide Phosphodiesterases, Type 7 - physiology; Disease Models, Animal; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Glycogen Synthase Kinase 3 - metabolism; Internal Medicine; Male; Mice; Mice, Transgenic; Molecular Targeted Therapy; Neurology; Phosphodiesterase inhibitors; Phosphorylation - drug effects; Quinazolines - pharmacology; Quinazolines - therapeutic use; Rats; Rats, Wistar; Signal Transduction - physiology; tau Proteins - metabolism; Transgenic mice
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2013.03.011

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.