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

Perez-Gonzalez, Rocio ; Pascual, Consuelo ; Antequera, Desiree ; Bolos, Marta ; Redondo, Miriam ; Perez, Daniel I ; Pérez-Grijalba, Virginia ; Krzyzanowska, Agnieszka LU ; Sarasa, Manuel and Gil, Carmen , et al. (2013) In Neurobiology of Aging 34(9). p.2133-2145
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alzheimer Disease/drug therapy, Amyloid beta-Peptides/metabolism, Animals, Astrocytes/metabolism, Behavior/drug effects, Cells, Cultured, Cognition/drug effects, Cyclic AMP/physiology, Cyclic AMP Response Element-Binding Protein/physiology, Cyclic Nucleotide Phosphodiesterases, Type 7/antagonists & inhibitors, Disease Models, Animal, Enzyme Inhibitors/pharmacology, Glycogen Synthase Kinase 3/metabolism, Male, Mice, Mice, Transgenic, Molecular Targeted Therapy, Phosphorylation/drug effects, Quinazolines/pharmacology, Rats, Rats, Wistar, Signal Transduction/physiology, tau Proteins/metabolism
in
Neurobiology of Aging
volume
34
issue
9
pages
2133 - 2145
publisher
Elsevier
external identifiers
  • scopus:84878926831
  • pmid:23582662
ISSN
1558-1497
DOI
10.1016/j.neurobiolaging.2013.03.011
language
English
LU publication?
no
id
822efb08-6d78-4f51-9c07-b426861f523f
date added to LUP
2018-08-27 13:56:40
date last changed
2024-03-01 23:28:12
@article{822efb08-6d78-4f51-9c07-b426861f523f,
  abstract     = {{<p>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.</p>}},
  author       = {{Perez-Gonzalez, Rocio and Pascual, Consuelo and Antequera, Desiree and Bolos, Marta and Redondo, Miriam and Perez, Daniel I and Pérez-Grijalba, Virginia and Krzyzanowska, Agnieszka and Sarasa, Manuel and Gil, Carmen and Ferrer, Isidro and Martinez, Ana and Carro, Eva}},
  issn         = {{1558-1497}},
  keywords     = {{Alzheimer Disease/drug therapy; Amyloid beta-Peptides/metabolism; Animals; Astrocytes/metabolism; Behavior/drug effects; Cells, Cultured; Cognition/drug effects; Cyclic AMP/physiology; Cyclic AMP Response Element-Binding Protein/physiology; Cyclic Nucleotide Phosphodiesterases, Type 7/antagonists & inhibitors; Disease Models, Animal; Enzyme Inhibitors/pharmacology; Glycogen Synthase Kinase 3/metabolism; Male; Mice; Mice, Transgenic; Molecular Targeted Therapy; Phosphorylation/drug effects; Quinazolines/pharmacology; Rats; Rats, Wistar; Signal Transduction/physiology; tau Proteins/metabolism}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{2133--2145}},
  publisher    = {{Elsevier}},
  series       = {{Neurobiology of Aging}},
  title        = {{Phosphodiesterase 7 inhibitor reduced cognitive impairment and pathological hallmarks in a mouse model of Alzheimer's disease}},
  url          = {{http://dx.doi.org/10.1016/j.neurobiolaging.2013.03.011}},
  doi          = {{10.1016/j.neurobiolaging.2013.03.011}},
  volume       = {{34}},
  year         = {{2013}},
}