DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes

Peter Sykora, Magdalena Misiak, Yue Wang, Somnath Ghosh, Giovana S. Leandro, Dong Liu, Jane Tian, Beverly A. Baptiste, Wei Na Cong, Boris M. Brenerman, Evandro Fang, Kevin G. Becker, Royce J. Hamilton, Soumya Chigurupati, Yongqing Zhang, Josephine M. Egan, Deborah L. Croteau, David M. Wilson, Mark P. Mattson, Vilhelm A. Bohr

Research output: Contribution to journalArticle

Abstract

We explore the role of DNA damage processing in the progression of cognitive decline by creating a new mouse model. The new model is a cross of a common Alzheimer's disease (AD) mouse (3xTgAD), with a mouse that is heterozygous for the critical DNA base excision repair enzyme, DNA polymerase β. A reduction of this enzyme causes neurodegeneration and aggravates the AD features of the 3xTgAD mouse, inducing neuronal dysfunction, cell death and impairing memory and synaptic plasticity. Transcriptional profiling revealed remarkable similarities in gene expression alterations in brain tissue of human AD patients and 3xTg/Polβ+/- mice including abnormalities suggestive of impaired cellular bioenergetics. Our findings demonstrate that a modest decrement in base excision repair capacity can render the brain more vulnerable to AD-related molecular and cellular alterations.

Original languageEnglish (US)
Pages (from-to)943-959
Number of pages17
JournalNucleic Acids Research
Volume43
Issue number2
DOIs
StatePublished - Jan 30 2015
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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  • Cite this

    Sykora, P., Misiak, M., Wang, Y., Ghosh, S., Leandro, G. S., Liu, D., Tian, J., Baptiste, B. A., Cong, W. N., Brenerman, B. M., Fang, E., Becker, K. G., Hamilton, R. J., Chigurupati, S., Zhang, Y., Egan, J. M., Croteau, D. L., Wilson, D. M., Mattson, M. P., & Bohr, V. A. (2015). DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes. Nucleic Acids Research, 43(2), 943-959. https://doi.org/10.1093/nar/gku1356