Molecular signatures of neurodegeneration in the cortex of PS1/PS2 double knockout mice

Karoly Mirnics, Eric M. Norstrom, Krassimira Garbett, Se Hoon Choi, Xiaoqiong Zhang, Philip Ebert, Sangram S. Sisodia

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background. Familial Alzheimer's disease-linked variants of presenilin (PSEN1 and PSEN2) contribute to the pathophysiology of disease by both gain-of-function and loss-of-function mechanisms. Deletions of PSEN1 and PSEN2 in the mouse forebrain result in a strong and progressive neurodegenerative phenotype which is characterized by both anatomical and behavioral changes. Results. To better understand the molecular changes associated with these morphological and behavioral phenotypes, we performed a DNA microarray transcriptome profiling of the hippocampus and the frontal cortex of the PSEN1/PSEN2 double knock-out mice and littermate controls at five different ages ranging from 2-8 months. Our data suggest that combined deficiencies of PSEN1 and PSEN2 results in a progressive, age-dependent transcriptome signature related to neurodegeneration and neuroinflammation. While these events may progress differently in the hippocampus and frontal cortex, the most critical expression signatures are common across the two brain regions, and involve a strong upregulation of cathepsin and complement system transcripts. Conclusion. The observed neuroinflammatory expression changes are likely to be causally linked to the neurodegenerative phenotype observed in mice with compound deletions of PSEN1 and PSEN2. Furthermore, our results suggest that the evaluation of inhibitors of PS/γ-secretase activity for treatment of Alzheimer's Disease must include close monitoring for signs of calpain-cathepsin system activation.

Original languageEnglish (US)
Article number14
JournalMolecular Neurodegeneration
Volume3
Issue number1
DOIs
StatePublished - Oct 23 2008

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Knockout Mice
Cathepsins
Frontal Lobe
Phenotype
Hippocampus
Alzheimer Disease
Presenilins
Amyloid Precursor Protein Secretases
Calpain
Gene Expression Profiling
Prosencephalon
Oligonucleotide Array Sequence Analysis
Transcriptome
Up-Regulation
Brain

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Molecular signatures of neurodegeneration in the cortex of PS1/PS2 double knockout mice. / Mirnics, Karoly; Norstrom, Eric M.; Garbett, Krassimira; Choi, Se Hoon; Zhang, Xiaoqiong; Ebert, Philip; Sisodia, Sangram S.

In: Molecular Neurodegeneration, Vol. 3, No. 1, 14, 23.10.2008.

Research output: Contribution to journalArticle

Mirnics, Karoly ; Norstrom, Eric M. ; Garbett, Krassimira ; Choi, Se Hoon ; Zhang, Xiaoqiong ; Ebert, Philip ; Sisodia, Sangram S. / Molecular signatures of neurodegeneration in the cortex of PS1/PS2 double knockout mice. In: Molecular Neurodegeneration. 2008 ; Vol. 3, No. 1.
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