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Overexpression of wild-type human APP in mice causes cognitive deficits and pathological features unrelated to Aβ levels
Authors:Ana-Marí  a Sim  n, Lucio Schiapparelli, Pablo Salazar-Colocho, Mar Cuadrado-Tejedor, Luis Escribano, Rakel L  pez de Maturana, Joaquí  n Del Rí  o, Alberto P  rez-Mediavilla,Diana Frechilla
Affiliation:aDivision of Neurosciences, CIMA, University of Navarra, Av. Pio XII 55, 31008 Pamplona, Spain;bCIBERNED, Spain
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.
Keywords:Alzheimer's disease   APP   Amyloid   Tau   Synapse   Hippocampus   Memory
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