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.