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The Journal of Neuroscience, February 9, 2005, 25(6):1571-1578; doi:10.1523/JNEUROSCI.4145-04.2005

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Neurobiology of Disease
Presenilin-1-Dependent Transcriptome Changes

Károly Mirnics,^1,2 * Zeljka Korade,^3 * Dominique Arion,¹ Orly Lazarov,⁴ Travis Unger,¹ Melissa Macioce,¹ Michael Sabatini,^1,2 David Terrano,⁴ Katherine C. Douglass,¹ Nina F. Schor,³ and Sangram S. Sisodia⁴

Departments of ¹Psychiatry, ²Neurobiology, and ³Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, and ⁴Center for Molecular Neurobiology, University of Chicago, Chicago, Illinois 60637

Familial forms of Alzheimer's disease (FADs) are caused by the expression of mutant presenilin 1 (PS1) or presenilin 2. Using DNA microarrays, we explored the brain transcription profiles of mice with conditional knock-out of PS1 (cKO PS1) in the forebrain. In parallel, we performed a transcription profiling of the hippocampus and frontal cortex of the FAD-linked E9 mutant transgenic (TG) mice and matched controls [TG mice expressing wild-type human PS1 (hPS1)]. When the TG and cKO datasets were cross-compared, the majority of the 30 common expression alterations were in opposite direction, suggesting that the FAD-linked PS1 variant produces transcriptome changes primarily by gain of aberrant function. Our microarray studies also revealed an unanticipated inverse correlation of transcript levels between the brains of mice that coexpress E9 hPS1+ amyloid precursor protein (APP)₆₉₅ Swe and E9 hPS1 single transgenic mice. The opposite directionality of these changes in transcript levels must be a function of APP and/or APP derivatives.

Key words: presenilin; DNA microarray; Alzheimer's disease; gene expression; transcriptome; animal model

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Received Oct 6, 2004; revised December 10, 2004; accepted December 11, 2004.

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