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Treatment with a serotonin 5-HT4-receptor agonist ameliorates cognitive deficits and amyloid pathology in the 3xTg-AD model of Alzheimer's disease

AuthorsGarcía-Miralles, A. ; Giménez-Llort, Lydia; Porcar, I. ; LaFerla, Frank M.; Vilaró, Maria Teresa
Issue Date10-Jul-2012
CitationI CIBICAT (2012)
AbstractAlzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular neuritic plaques of amyloid-beta peptide (Aβ), non-fibrilar intraneuronal soluble forms of Aβ and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. Aβ is generated from its precursor protein APP after cleavage by β- and γ-secretases. In contrast, cleavage of APP by α-secretase releases the soluble, non-amyloidogenic peptide sAPPα. Activation of serotonin 5-HT4 receptors enhances APP processing by α-secretase, thus increasing sAPPα levels in vitro and in vivo. The triple transgenic mouse model of AD (3xTg-AD), harboring the APPSwe, PS1M146V and tauP301L mutant genes, mimics critical aspects of AD neuropathology including learning and memory deficits. We have studied in this model the effect of chronic stimulation of 5-HT4 receptors on APP processing, Aβ pathology, cognitive deficits and other behavioral symptoms. Six month-old male and 12 month-old female 3xTg-AD mice and age-matched wild-type (wt) animals were given the 5-HT4 partial agonist RS67333 or its vehicle using osmotic minipumps. Spatial learning and memory in the Morris Water Maze (MWM) were unaltered in 6 months-old 3xTg-AD males but severely impaired in 12 month-old 3xTg-AD females compared with age- and sex-matched wt controls. These deficits were rescued by agonist administration: agonist-treated 3xTg-AD mice performed as well as vehicle-treated wt controls. The anxious profile of 3xTg-AD mice in the Open Field and Dark/Light Box tests at both ages, showed a tendency to recovery after treatment with RS67333. Immunohistochemical analysis revealed marked decreases of extracellular amyloid plaques in the subiculum of 12 month-old agonist-treated 3xTg-AD animals compared with vehicle-treated 3xTg-AD animals. These results suggest that sustained activation of 5-HT4 receptors may be beneficial to counteract the cognitive deficits and to ammeliorate Aβ pathology in this model of AD.
DescriptionTrabajo presentado al I Congrés Internacional de Biologia de Catalunya: Global questions on advanced biology, celebrado en Barcelona del 9 al 12 de julio de 2012.
Appears in Collections:(IIBB) Comunicaciones congresos
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