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Nucleic Acids Res. 2015 Jan;43(2):943-59. doi: 10.1093/nar/gku1356. Epub 2014 Dec 30.

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

Author information

1
Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD 21224, USA.
2
Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD 21224, USA Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD 21224, USA.
3
Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD 21224, USA.
4
Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD 21224, USA Laboratory of Genetics, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD 21224, USA.
5
Laboratory of Clinical Investigation, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD 21224, USA.
6
Department of Genetics, Ribeirao Preto Medical School, University of Sao Paulo-Ribeirao Preto, SP 14049-900, Brazil.
7
Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD 21224, USA vbohr@nih.gov.

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.

PMID:
25552414
PMCID:
PMC4333403
DOI:
10.1093/nar/gku1356
[Indexed for MEDLINE]
Free PMC Article

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