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Overexpression of wild-type human APP in mice causes cognitive déficits and pathological features unrelated to Abeta levels
Authors: Simon, A.M. (Ana María)
Schiapparelli, L. (Lucio)
Salazar-Colocho, P. (Pablo)
Cuadrado-Tejedor, M. (Mar)
Escribano, L. (L.)
Lopez-de-Maturana, R. (Rakel)
Rio, J. (Joaquín) del
Perez-Mediavilla, L.A. (Luis Alberto)
Frechilla, D. (Diana)
Keywords: Alzheimer's disease
Memory
Hippocampus
Synapse
Tau
Amyloid
APP
Issue Date: Mar-2009
Publisher: Elsevier
Publisher version: http://dx.doi.org/10.1016/j.nbd.2008.11.005
ISSN: 0969-9961
Citation: Simon AM, Schiapparelli L, Salazar-Colocho P, Cuadrado-Tejedor M, Escribano L, Lopez de Maturana R, et al. Overexpression of wild-type human APP in mice causes cognitive deficits and pathological features unrelated to Abeta levels. Neurobiol Dis 2009 Mar;33(3):369-378.
Abstract
Transgenic mice expressing mutant human amyloid precursor protein (APP) develop an age-dependent amyloid pathology and memory deficits, but no overt neuronal loss. Here, in mice overexpressing wild-type human APP (hAPPwt) we found an early memory impairment, particularly in the water maze and to a lesser extent in the object recognition task, but β-amyloid peptide (Aβ42) was barely detectable in the hippocampus. In these mice, hAPP processing was basically non-amyloidogenic, with high levels of APP carboxy-terminal fragments, C83 and APP intracellular domain. A tau pathology with an early increase in the levels of phosphorylated tau in the hippocampus, a likely consequence of enhanced ERK1/2 activation, was also observed. Furthermore, these mice presented a loss of synapse-associated proteins: PSD95, AMPA and NMDA receptor subunits and phosphorylated CaMKII. Importantly, signs of neurodegeneration were found in the hippocampal CA1 subfield and in the entorhinal cortex that were associated to a marked loss of MAP2 immunoreactivity. Conversely, in mice expressing mutant hAPP, high levels of Aβ42 were found in the hippocampus, but no signs of neurodegeneration were apparent. The results support the notion of Aβ- independent pathogenic pathways in Alzheimer's disease.
Permanent link: http://hdl.handle.net/10171/16499
Appears in Collections:DA - Ciencias - HAP - Artículos de revista
DA - Ciencias - Bioquímica y Biología molecular - Artículos de Revista
DA - CIMA - Neurociencias - Neurofarmacología y conducta - Artículos de Revista

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