Reduced beta-amyloid production and increased inflammatory responses in presenilin conditional knock-out mice.
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 beta-amyloid (Abeta) peptides in the cerebral cortex of PS cDKO mice. Interestingly, the reduction in Abeta40 and Abeta42 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 Abeta accumulation and that loss of PS function leads to differential up-regulation of inflammatory markers in the cerebral cortex.
Beglopoulos
Vassilios
V
Center for Neurologic Diseases, Brigham and Women's Hospital, Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, USA.
Sun
Xiaoyan
X
Saura
Carlos A
CA
Lemere
Cynthia A
CA
Kim
Richard D
RD
Shen
Jie
J
D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002403:Cathepsins / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D015922:Complement C1q / Q000378:metabolism; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics*; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D019636:Neurodegenerative Diseases / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010455:Peptides / Q000737:chemistry; D010641:Phenotype; D053764:Presenilin-1; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D016229:Amyloid beta-Peptides; D005904:Glial Fibrillary Acidic Protein; D008565:Membrane Proteins; D010455:Peptides; D053764:Presenilin-1; D012333:RNA, Messenger; D015922:Complement C1q; D017493:Leukocyte Common Antigens; D002403:Cathepsins; C028217:cathepsin S