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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2008-12

AUTHORS

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

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/gamma-secretase activity for treatment of Alzheimer's Disease must include close monitoring for signs of calpain-cathepsin system activation. More... »

PAGES

14

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/1750-1326-3-14

DOI

http://dx.doi.org/10.1186/1750-1326-3-14

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1006464471

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/18834536


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