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The Journal of Neuroscience, July 20, 2005, 25(29):6755-6764; doi:10.1523/JNEUROSCI.1247-05.2005

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Neurobiology of Disease
Conditional Inactivation of Presenilin 1 Prevents Amyloid Accumulation and Temporarily Rescues Contextual and Spatial Working Memory Impairments in Amyloid Precursor Protein Transgenic Mice

Carlos A. Saura,¹ Guiquan Chen,² Seema Malkani,¹ Se-Young Choi,³ Reisuke H. Takahashi,⁴ Dawei Zhang,¹ Gunnar K. Gouras,⁴ Alfredo Kirkwood,³ Richard G. M. Morris,² and Jie Shen¹

¹Center for Neurologic Diseases, Brigham and Women's Hospital and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, ²Laboratory for Cognitive Neuroscience, The University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom, ³Mind/Brain Institute, Johns Hopkins University, Baltimore, Maryland 21218, and ⁴Department of Neurology and Neuroscience, Cornell Medical School, New York, New York 10021

Accumulation of -amyloid (A) peptides in the cerebral cortex is considered a key event in the pathogenesis of Alzheimer's 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 of A 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.

Key words: Alzheimer's disease; -amyloid; -secretase; mouse; behavior; synaptic plasticity

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Received March 31, 2005; revised June 1, 2005; accepted June 1, 2005.

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