Reduced β-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, Jie Shen

Research output: Contribution to journalArticle

107 Citations (Scopus)

Abstract

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 β-amyloid (Aβ) peptides in the cerebral cortex of PS cDKO mice. Interestingly, the reduction in Aβ40 and Aβ42 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 Aβ accumulation and that loss of PS function leads to differential up-regulation of inflammatory markers in the cerebral cortex.

Original languageEnglish (US)
Pages (from-to)46907-46914
Number of pages8
JournalJournal of Biological Chemistry
Volume279
Issue number45
DOIs
StatePublished - Nov 5 2004
Externally publishedYes

Fingerprint

Presenilins
Amyloid
Knockout Mice
cathepsin S
Cerebral Cortex
Complement C1q
Hippocampus
Glial Fibrillary Acidic Protein
Up-Regulation
Genes
Presenilin-2
Presenilin-1
Data storage equipment
Immunosorbents
Neuronal Plasticity
Poisons
Protein S
Neocortex
Transcription
Microarrays

ASJC Scopus subject areas

  • Biochemistry

Cite this

Reduced β-amyloid production and increased inflammatory responses in presenilin conditional knock-out mice. / Beglopoulos, Vassilios; Sun, Xiaoyan; Saura, Carlos A.; Lemere, Cynthia A.; Kim, Richard D.; Shen, Jie.

In: Journal of Biological Chemistry, Vol. 279, No. 45, 05.11.2004, p. 46907-46914.

Research output: Contribution to journalArticle

Beglopoulos, Vassilios ; Sun, Xiaoyan ; Saura, Carlos A. ; Lemere, Cynthia A. ; Kim, Richard D. ; Shen, Jie. / Reduced β-amyloid production and increased inflammatory responses in presenilin conditional knock-out mice. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 45. pp. 46907-46914.
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