title: Overexpression of wild-type human APP in mice causes cognitive deficits and pathological features unrelated to Abeta levels.
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 (hAPP(wt)) we found an early memory impairment, particularly in the water maze and to a lesser extent in the object recognition task, but beta-amyloid peptide (Abeta(42)) 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 Abeta(42) were found in the hippocampus, but no signs of neurodegeneration were apparent. The results support the notion of Abeta-independent pathogenic pathways in Alzheimer's disease.
authors.affiliation: Division of Neurosciences, CIMA, University of Navarra, Av. Pio XII 55, 31008 Pamplona, Spain.
authors.forename: Ana-María
authors.initials: AM
authors.lastname: Simón
authors.forename: Lucio
authors.initials: L
authors.lastname: Schiapparelli
authors.forename: Pablo
authors.initials: P
authors.lastname: Salazar-Colocho
authors.forename: Mar
authors.initials: M
authors.lastname: Cuadrado-Tejedor
authors.forename: Luis
authors.initials: L
authors.lastname: Escribano
authors.forename: Rakel
authors.initials: R
authors.lastname: López de Maturana
authors.forename: Joaquín
authors.initials: J
authors.lastname: Del Río
authors.forename: Alberto
authors.initials: A
authors.lastname: Pérez-Mediavilla
authors.forename: Diana
authors.initials: D
authors.lastname: Frechilla
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D003071:Cognition / Q000502:physiology*; D000076122:Disks Large Homolog 4 Protein; D051528:Guanylate Kinases; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D018782:Maze Learning; D008565:Membrane Proteins / Q000378:metabolism; D008568:Memory; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D010446:Peptide Fragments / Q000378:metabolism*; D010766:Phosphorylation; D058255:Protease Nexins; D018091:Receptors, AMPA / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D021641:Recognition, Psychology; D013569:Synapses / Q000502:physiology; D016875:tau Proteins / Q000378:metabolism
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D010446:Peptide Fragments; D058255:Protease Nexins; D018091:Receptors, AMPA; D011956:Receptors, Cell Surface; D016194:Receptors, N-Methyl-D-Aspartate; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D051528:Guanylate Kinases