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J. Biol. Chem., Vol. 279, Issue 45, 46907-46914, November 5, 2004

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Reduced -Amyloid Production and Increased Inflammatory Responses in Presenilin Conditional Knock-out Mice^*

Vassilios Beglopoulos, Xiaoyan Sun, Carlos A Saura, Cynthia A. Lemere, Richard D. Kim¶, and Jie Shen||

From the Center for Neurologic Diseases, Brigham and Women's Hospital, Program in Neuroscience, Harvard Medical School and the ^¶Harvard-Partners Center for Genetics and Genomics, Boston, Massachusetts 02115

Mutations in presenilins (PS) 1 and 2 are the major cause of familial Alzheimer's disease. Conditional double knock-out mice lacking both presenilins in the postnatal forebrain (PS cDKO mice) exhibit memory and synaptic plasticity impairments followed by progressive neurodegeneration in the cerebral cortex. Here we further investigate the molecular events that may underlie the observed phenotypes and identify additional neuropathological markers in the PS cDKO brain. Enzyme-linked immunosorbent assay analysis showed reduced levels of the toxic -amyloid (A) peptides in the cerebral cortex of PS cDKO mice. Interestingly, the reduction in A40 and A42 peptides is similar in PS1 conditional knock-out and PS cDKO mice. We further examined the gene expression profile by oligonucleotide microarrays in the PS cDKO cerebral cortex and found that a high number of genes are differentially expressed, most notably a group of up-regulated inflammatory genes. Quantitative real-time reverse transcription PCR and Western analyses confirmed the elevated levels of glial fibrillary acidic protein, complement component C1q, and cathepsin S, up-regulation of which has been associated with inflammatory responses in various neurodegenerative processes. Immunohistochemical analysis revealed that the increase in complement component C1q is confined to the hippocampal formation, whereas glial fibrillary acidic protein and cathepsin S are up-regulated throughout the entire neocortex and hippocampus. In addition, strong microglial activation occurs in the hippocampus and the deeper cortical layers of PS cDKO mice. These results indicate that the memory impairment and neurodegeneration in PS cDKO mice are not caused by A accumulation and that loss of PS function leads to differential up-regulation of inflammatory markers in the cerebral cortex.

Received for publication, August 19, 2004

^* This work was supported by a National Institutes of Health Grant NS41783. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

^|| To whom correspondence should be addressed: Center for Neurologic Diseases, Harvard New Research Bldg. 636E, 77 Ave. Louis Pasteur, Boston, MA 02115. Tel.: 617-525-5561; Fax: 617-525-5522; E-mail: jshen{at}rics.bwh.harvard.edu.

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