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