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Conditional inactivation of presenilin 1 prevents amyloid accumulation and temporarily rescues contextual and spatial working memory impairments in amyloid precursor protein transgenic mice.

Cited 127 time in Web of Science Cited 134 time in Scopus
Authors
Saura, Carlos A.; Chen, Guiquan; Malkani, Seema; Choi, Se-Young; Takahashi, Reisuke H.; Zhang, Dawei; Gouras, Gunnar K.; Kirkwood, Alfredo; Morris, Richard G. M.; Shen, Jie
Issue Date
2005-07-20
Publisher
Society for Neuroscience
Citation
The Journal of Neuroscience, 2005;25(29):6755– 6764
Keywords
Alzheimer’s diseaseβ-amyloidγ-secretasemousebehaviorsynaptic plasticity
Abstract
Accumulation of -amyloid (A ) peptides in the cerebral cortex is considered a key event in the pathogenesis of Alzheimers disease
(AD). Presenilin 1 (PS1) plays an essential role in the -secretase cleavage of the amyloid precursor protein (APP) and the generation of
A peptides. Reduction of A generation via the inhibition of -secretase activity, therefore, has been proposed as a therapeutic
approach for AD. In this study, we examined whether genetic inactivation of PS1 in postnatal forebrain-restricted conditional knock-out
(PS1 cKO) mice can prevent the accumulation ofA peptides and ameliorate cognitive deficits exhibited by an amyloid mouse model that
overexpresses human mutant APP. We found that conditional inactivation of PS1 in APP transgenic mice (PS1 cKO;APP Tg) effectively
prevented the accumulation of A peptides and formation of amyloid plaques and inflammatory responses, although it also caused an
age-related accumulation of C-terminal fragments of APP. Short-term PS1 inactivation in young PS1 cKO;APP Tg mice rescued deficits in
contextual fear conditioning and serial spatial reversal learning in a water maze, which were associated with APP Tg mice. Longer-term
PS1 inactivation in older PS1 cKO;APP Tg mice, however, failed to rescue the contextual memory and hippocampal synaptic deficits and
had a decreasing ameliorative effect on the spatial memory impairment. These results reveal that in vivo reduction of A via the
inactivation of PS1 effectively prevents amyloid-associated neuropathological changes and can, but only temporarily, improve cognitive
impairments in APP transgenic mice.
Language
English
URI
https://hdl.handle.net/10371/63274
DOI
https://doi.org/10.1523/JNEUROSCI.1247-05.2005
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College of Dentistry/School of Dentistry (치과대학/치의학대학원)Dept. of Dentistry (치의학과)Journal Papers (저널논문_치의학과)
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