期刊
NEUROBIOLOGY OF DISEASE
卷 33, 期 3, 页码 369-378出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2008.11.005
关键词
Alzheimer's disease; APP; Amyloid; Tau; Synapse; Hippocampus; Memory
资金
- Ministry of Education and Science [SAF-2005-05086, SAF-2008-02342]
- Ministry of Health (CIBERNED), Spain
- LITE project FIMA
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 (A beta(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 A beta(42) were found in the hippocampus, but no signs of neurodegeneration were apparent. The results support the notion of A beta-independent pathogenic pathways in Alzheimer's disease. (C) 2008 Elsevier Inc. All rights reserved.
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