title: DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes.
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.
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD 21224, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Sykora
authors.affiliation: 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.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Misiak
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD 21224, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD 21224, USA.
authors.forename: Somnath
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: 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.
authors.forename: Giovana S
authors.initials: GS
authors.lastname: Leandro
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD 21224, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD 21224, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Tian
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD 21224, USA.
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Baptiste
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD 21224, USA.
authors.forename: Wei-Na
authors.initials: WN
authors.lastname: Cong
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD 21224, USA.
authors.forename: Boris M
authors.initials: BM
authors.lastname: Brenerman
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD 21224, USA.
authors.forename: Evandro
authors.initials: E
authors.lastname: Fang
authors.affiliation: Department of Genetics, Ribeirao Preto Medical School, University of Sao Paulo-Ribeirao Preto, SP 14049-900, Brazil.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Becker
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD 21224, USA.
authors.forename: Royce J
authors.initials: RJ
authors.lastname: Hamilton
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD 21224, USA.
authors.forename: Soumya
authors.initials: S
authors.lastname: Chigurupati
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD 21224, USA.
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Laboratory of Clinical Investigation, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD 21224, USA.
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Egan
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD 21224, USA.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Croteau
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD 21224, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Wilson
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD 21224, USA.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, Intramural Research Program (NIA IRP), Biomedical Research Center, Baltimore, MD 21224, USA vbohr@nih.gov.
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D019951:DNA Polymerase beta / Q000235:genetics*; D004260:DNA Repair; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005260:Female; D006579:Heterozygote; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D059467:Transcriptome
chemical_list: D016229:Amyloid beta-Peptides; D019951:DNA Polymerase beta