Accumulation of β-amyloid (Aβ) 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 γ-secretase cleavage of the amyloid precursor protein (APP) and the generation of Aβ peptides. Reduction of Aβ generation via the inhibition of γ-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 (PS1cKO) mice can prevent the accumulation of Aβ peptides and ameliorate cognitive deficits exhibited by an amyloid mouse model that overexpresses human mutant APP. We found that conditional inactivation of PS1 inAPPtransgenic mice (PS1cKO;APPTg) effectively prevented the accumulation of Aβ 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 youngPS1cKO;APPTg mice rescued deficits in contextual fear conditioning and serial spatial reversal learning in a water maze, which were associated withAPPTg mice. Longer-term PS1 inactivation in olderPS1cKO;APPTg 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 thatin vivoreduction of Aβ via the inactivation of PS1 effectively prevents amyloid-associated neuropathological changes and can, but only temporarily, improve cognitive impairments inAPPtransgenic mice.

Saura, C. A., Chen, G., Malkani, S., Choi, S.-Y., Takahashi, R. H., Zhang, D., Gouras, G. K., Kirkwood, A., Morris, R. G. M., & Shen, J. (2005). Conditional Inactivation of Presenilin 1 Prevents Amyloid Accumulation and Temporarily Rescues Contextual and Spatial Working Memory Impairments in Amyloid Precursor Protein Transgenic Mice. The Journal of Neuroscience, 25(29), 6755–6764.