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

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.

[1]  BDNF and Exercise Enhance Neuronal DNA Repair by Stimulating CREB-Mediated Production of Apurinic/Apyrimidinic Endonuclease 1 , 2014, NeuroMolecular Medicine.

[2]  Samuel H. Wilson,et al.  Mammalian Abasic Site Base Excision Repair , 1998, The Journal of Biological Chemistry.

[3]  W. Markesbery,et al.  Ratio of 8-hydroxyguanine in intact DNA to free 8-hydroxyguanine is increased in Alzheimer disease ventricular cerebrospinal fluid. , 2001, Archives of neurology.

[4]  T. Saido,et al.  Dual roles for autophagy: Degradation and secretion of Alzheimer's disease Aβ peptide , 2014, BioEssays : news and reviews in molecular, cellular and developmental biology.

[5]  M. Bjørås,et al.  Endonuclease VIII-like 3 (Neil3) DNA glycosylase promotes neurogenesis induced by hypoxia-ischemia , 2011, Proceedings of the National Academy of Sciences.

[6]  M. Mattson,et al.  Mitochondria in Neuroplasticity and Neurological Disorders , 2008, Neuron.

[7]  M. Mattson,et al.  Intermittent fasting and caloric restriction ameliorate age-related behavioral deficits in the triple-transgenic mouse model of Alzheimer's disease , 2007, Neurobiology of Disease.

[8]  M. Katz,et al.  What is lipofuscin? Defining characteristics and differentiation from other autofluorescent lysosomal storage bodies. , 2002, Archives of gerontology and geriatrics.

[9]  N. S. Raji,et al.  Trisomy 21 and accelerated aging: DNA-repair parameters in peripheral lymphocytes of Down's syndrome patients , 1998, Mechanisms of Ageing and Development.

[10]  R. Hamilton,et al.  Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease , 2009, Proceedings of the National Academy of Sciences.

[11]  M. Mattson,et al.  Defective DNA base excision repair in brain from individuals with Alzheimer's disease and amnestic mild cognitive impairment , 2007, Nucleic acids research.

[12]  M. Lovell,et al.  Nucleic acid oxidation: an early feature of Alzheimer's disease , 2014, Journal of neurochemistry.

[13]  V. Bohr,et al.  Base excision DNA repair levels in mitochondrial lysates of Alzheimer's disease , 2014, Neurobiology of Aging.

[14]  M. Lovell,et al.  Oxidatively modified nucleic acids in preclinical Alzheimer's disease (PCAD) brain , 2011, Mechanisms of Ageing and Development.

[15]  J. Feldon,et al.  Environmental enrichment eliminates the anxiety phenotypes in a triple transgenic mouse model of Alzheimer’s disease , 2014, Cognitive, affective & behavioral neuroscience.

[16]  V. Annapurna,et al.  DNA Polymerase‐β May Be the Main Player for Defective DNA Repair in Aging Rat Neurons , 2001, Annals of the New York Academy of Sciences.

[17]  J. Vijg,et al.  Studies on DNA repair defects in degenerative brain disease. , 1993, Age and ageing.

[18]  C. Bieberich,et al.  The Alzheimer's Aβ peptide induces neurodegeneration and apoptotic cell death in transgenic mice , 1995, Nature Genetics.

[19]  E. Englander,et al.  DNA polymerase β‐catalyzed‐PCNA independent long patch base excision repair synthesis: a mechanism for repair of oxidatively damaged DNA ends in post‐mitotic brain , 2008, Journal of neurochemistry.

[20]  A. Sigurdson,et al.  Variation in base excision repair capacity. , 2011, Mutation research.

[21]  T. Douki,et al.  Alzheimer’s Disease-Associated Neurotoxic Peptide Amyloid-β Impairs Base Excision Repair in Human Neuroblastoma Cells , 2012, International journal of molecular sciences.

[22]  Stuart Maudsley,et al.  Amitriptyline-Mediated Cognitive Enhancement in Aged 3×Tg Alzheimer's Disease Mice Is Associated with Neurogenesis and Neurotrophic Activity , 2011, PloS one.

[23]  F. Gage,et al.  Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus , 1999, Nature Neuroscience.

[24]  J. Octave,et al.  Intracellular amyloid-beta 1-42, but not extracellular soluble amyloid-beta peptides, induces neuronal apoptosis. , 2002, The Journal of biological chemistry.

[25]  T. Saido,et al.  Aβ secretion and plaque formation depend on autophagy. , 2013, Cell reports.

[26]  Y. Kubota,et al.  Neonatal lethality with abnormal neurogenesis in mice deficient in DNA polymerase β , 2000, The EMBO journal.

[27]  M. Hendzel,et al.  The gamma-H2A.X: is it just a surrogate marker of double-strand breaks or much more? , 2008, Environmental and molecular mutagenesis.

[28]  S. File,et al.  Validation of open : closed arm entries in an elevated plus-maze as a measure of anxiety in the rat , 1985, Journal of Neuroscience Methods.

[29]  N. Holbrook,et al.  Oxidants, oxidative stress and the biology of ageing , 2000, Nature.

[30]  D. C. Cabelof,et al.  Attenuation of DNA polymerase beta-dependent base excision repair and increased DMS-induced mutagenicity in aged mice. , 2002, Mutation research.

[31]  C. Jack,et al.  Rates of hippocampal atrophy correlate with change in clinical status in aging and AD , 2000, Neurology.

[32]  J. Cummings,et al.  Frequency and characteristics of anxiety among patients with Alzheimer's disease and related dementias. , 2003, The Journal of neuropsychiatry and clinical neurosciences.

[33]  J. Moriguti,et al.  Lymphocytes of Patients with Alzheimer’s Disease Display Different DNA Damage Repair Kinetics and Expression Profiles of DNA Repair and Stress Response Genes , 2013, International journal of molecular sciences.

[34]  M. Mattson,et al.  The plasma membrane redox system is impaired by amyloid β-peptide and in the hippocampus and cerebral cortex of 3xTgAD mice , 2010, Experimental Neurology.

[35]  D. Offen,et al.  Targeting neurogenesis ameliorates danger assessment in a mouse model of Alzheimer's disease , 2014, Behavioural Brain Research.

[36]  I. Kohane,et al.  Gene regulation and DNA damage in the ageing human brain , 2004, Nature.

[37]  A. Bacci,et al.  Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease , 2011, Nature Neuroscience.

[38]  Nils Z. Borgesius,et al.  Accelerated Age-Related Cognitive Decline and Neurodegeneration, Caused by Deficient DNA Repair , 2011, The Journal of Neuroscience.

[39]  David M. Wilson,et al.  Direct and indirect roles of RECQL4 in modulating base excision repair capacity. , 2009, Human molecular genetics.

[40]  W. Markesbery,et al.  Increased levels of 4-hydroxynonenal and acrolein in the brain in preclinical Alzheimer disease. , 2010, Free radical biology & medicine.

[41]  P. Vandenabeele,et al.  Depletion of Beclin-1 due to proteolytic cleavage by caspases in the Alzheimer's disease brain , 2011, Neurobiology of Disease.

[42]  H. Fukui,et al.  Mitochondrial DNA damage in a mouse model of Alzheimer's disease decreases amyloid beta plaque formation , 2013, Neurobiology of Aging.

[43]  M. Mattson,et al.  Triple-Transgenic Model of Alzheimer's Disease with Plaques and Tangles Intracellular Aβ and Synaptic Dysfunction , 2003, Neuron.

[44]  W. Markesbery,et al.  Increased Nuclear DNA Oxidation in the Brain in Alzheimer's Disease , 1998, Journal of neurochemistry.

[45]  W. Markesbery,et al.  Increased oxidative damage in nuclear and mitochondrial DNA in mild cognitive impairment , 2006, Journal of neurochemistry.

[46]  M. Mattson,et al.  The KATP channel activator diazoxide ameliorates amyloid-β and tau pathologies and improves memory in the 3xTgAD mouse model of Alzheimer's disease. , 2010, Journal of Alzheimer's disease : JAD.

[47]  W. Markesbery,et al.  Oxidatively modified RNA in mild cognitive impairment , 2008, Neurobiology of Disease.

[48]  M. Lovell,et al.  RNA Oxidation Adducts 8-OHG and 8-OHA Change with Aβ42 Levels in Late-Stage Alzheimer's Disease , 2011, PloS one.

[49]  M. Mattson,et al.  Nicotinamide forestalls pathology and cognitive decline in Alzheimer mice: evidence for improved neuronal bioenergetics and autophagy procession , 2013, Neurobiology of Aging.

[50]  Tomio Sasaki,et al.  Altered Expression of Diabetes-Related Genes in Alzheimer's Disease Brains: The Hisayama Study , 2013, Cerebral cortex.

[51]  H. Praag,et al.  Bridging animal and human models of exercise-induced brain plasticity , 2013, Trends in Cognitive Sciences.

[52]  W. Markesbery,et al.  Elevated 4-hydroxyhexenal in Alzheimer's disease (AD) progression , 2012, Neurobiology of Aging.

[53]  M. Mattson,et al.  Endonuclease VIII-like 1 (NEIL1) promotes short-term spatial memory retention and protects from ischemic stroke-induced brain dysfunction and death in mice , 2012, Proceedings of the National Academy of Sciences.

[54]  L. Tsai,et al.  DNA Damage and Its Links to Neurodegeneration , 2014, Neuron.

[55]  Ding-I Yang,et al.  NAD attenuates oxidative DNA damages induced by amyloid beta-peptide in primary rat cortical neurons , 2014, Free radical research.

[56]  D. Butterfield,et al.  Evidence of oxidative damage in Alzheimer's disease brain: central role for amyloid beta-peptide. , 2001, Trends in molecular medicine.

[57]  Paul S. Aisen,et al.  Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model , 2008, Brain Research.

[58]  R J Mark,et al.  Amyloid β-Peptide Impairs Glucose Transport in Hippocampal and Cortical Neurons: Involvement of Membrane Lipid Peroxidation , 1997, The Journal of Neuroscience.

[59]  T. Tønjum,et al.  Transient OGG1, APE1, PARP1 and Polβ expression in an Alzheimer's disease mouse model , 2013, Mechanisms of Ageing and Development.

[60]  M. Mattson,et al.  The AAA+ ATPase Thorase Regulates AMPA Receptor-Dependent Synaptic Plasticity and Behavior , 2011, Cell.

[61]  W. Markesbery,et al.  Oxidative DNA damage in mild cognitive impairment and late-stage Alzheimer's disease , 2007, Nucleic acids research.

[62]  D. Butterfield,et al.  Amyloid β‐Peptide(1‐42) Contributes to the Oxidative Stress and Neurodegeneration Found in Alzheimer Disease Brain , 2004, Brain pathology.

[63]  Z. Zhai,et al.  Nuclear entry of active caspase-3 is facilitated by its p3-recognition-based specific cleavage activity , 2010, Cell Research.

[64]  M A Lovell,et al.  Increased oxidative damage in nuclear and mitochondrial DNA in Alzheimer's disease , 2005, Journal of neurochemistry.

[65]  W. Markesbery,et al.  Altered 8-oxoguanine glycosylase in mild cognitive impairment and late-stage Alzheimer's disease brain. , 2008, Free radical biology & medicine.

[66]  Samuel H. Wilson,et al.  Haploinsufficiency in DNA polymerase beta increases cancer risk with age and alters mortality rate. , 2006, Cancer research.

[67]  I. Demuth,et al.  DNA-repair in mild cognitive impairment and Alzheimer's disease. , 2013, DNA repair.

[68]  J. Hoeijmakers.  DNA damage, aging, and cancer. , 2009, The New England journal of medicine.

[69]  C. Vorhees,et al.  Morris water maze: procedures for assessing spatial and related forms of learning and memory , 2006, Nature Protocols.

[70]  M. Otterlei,et al.  Mitochondrial base excision repair of uracil and AP sites takes place by single-nucleotide insertion and long-patch DNA synthesis. , 2008, DNA repair.

[71]  S. Rasmussen,et al.  Mortality associated with Down's syndrome in the USA from 1983 to 1997: a population-based study , 2002, The Lancet.

[72]  Samuel H. Wilson,et al.  Base excision repair deficiency caused by polymerase beta haploinsufficiency: accelerated DNA damage and increased mutational response to carcinogens. , 2003, Cancer research.

[73]  Gunnar Brunborg,et al.  High-throughput comet assay using 96 minigels. , 2013, Mutagenesis.

[74]  D. Butterfield,et al.  Proteomic identification of HNE-bound proteins in early Alzheimer disease: Insights into the role of lipid peroxidation in the progression of AD , 2009, Brain Research.

[75]  W. Markesbery,et al.  Oxidative damage in mild cognitive impairment and early Alzheimer's disease , 2007, Journal of neuroscience research.

[76]  Michael J. Hendzel,et al.  The γ‐H2A.X: Is it just a surrogate marker of double‐strand breaks or much more? , 2008 .

[77]  M. Mattson,et al.  Evidence that OGG1 Glycosylase Protects Neurons against Oxidative DNA Damage and Cell Death under Ischemic Conditions , 2011, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[78]  E. Cadenas,et al.  2-Deoxy-D-Glucose Treatment Induces Ketogenesis, Sustains Mitochondrial Function, and Reduces Pathology in Female Mouse Model of Alzheimer's Disease , 2011, PloS one.

[79]  David M. Wilson,et al.  Modulation of DNA base excision repair during neuronal differentiation , 2013, Neurobiology of Aging.

[80]  M. Krishna,et al.  DNA damage response signaling in lung adenocarcinoma A549 cells following gamma and carbon beam irradiation. , 2011, Mutation research.

[81]  J. Cummings,et al.  Alzheimer’s disease drug-development pipeline: few candidates, frequent failures , 2014, Alzheimer's Research & Therapy.

[82]  P. Yates,et al.  THE TOPOGRAPHY OF PLAQUES AND TANGLES IN DOWN'S SYNDROME PATIENTS OF DIFFERENT AGES , 1986, Neuropathology and applied neurobiology.

[83]  K. Rajewsky,et al.  Deletion of a DNA polymerase beta gene segment in T cells using cell type-specific gene targeting. , 1994, Science.

[84]  L. Tran,et al.  Integrated Systems Approach Identifies Genetic Nodes and Networks in Late-Onset Alzheimer’s Disease , 2013, Cell.

[85]  W. Markesbery,et al.  DNA oxidation in Alzheimer's disease. , 2006, Antioxidants & redox signaling.

[86]  Anatol C. Kreitzer,et al.  Physiological Brain Activity Causes DNA Double Strand Breaks in Neurons — Exacerbation by Amyloid-β , 2013, Nature Neuroscience.

[87]  W. Markesbery,et al.  Increased DNA Oxidation and Decreased Levels of Repair Products in Alzheimer's Disease Ventricular CSF , 1999, Journal of neurochemistry.

[88]  K. Becker,et al.  Sporadic Alzheimer disease fibroblasts display an oxidative stress phenotype. , 2012, Free radical biology & medicine.

[89]  I. V. Kovtun,et al.  Cockayne Syndrome B protein antagonizes OGG1 in modulating CAG repeat length in vivo , 2011, Aging.

[90]  L. Brace,et al.  Defective Mitophagy in XPA via PARP-1 Hyperactivation and NAD+/SIRT1 Reduction , 2014, Cell.

[91]  J. Shoffner.  Oxidative phosphorylation defects and Alzheimer's disease , 1997, Neurogenetics.

[92]  V. Bohr,et al.  Base excision repair in the mammalian brain: Implication for age related neurodegeneration , 2013, Mechanisms of Ageing and Development.

[93]  H. Wiśniewski,et al.  Alzheimer's disease in Down's syndrome , 1985, Neurology.

[94]  M. Maiuri,et al.  Cross talk between apoptosis and autophagy by caspase-mediated cleavage of Beclin 1 , 2010, Oncogene.

[95]  E. Mullaart,et al.  Increased levels of DNA breaks in cerebral cortex of Alzheimer's disease patients , 1990, Neurobiology of Aging.

[96]  W. Markesbery,et al.  Increased levels of 4-hydroxynonenal and acrolein, neurotoxic markers of lipid peroxidation, in the brain in Mild Cognitive Impairment and early Alzheimer's disease , 2006, Neurobiology of Aging.

[97]  I. Driscoll,et al.  Asymptomatic Alzheimer's disease: a prodrome or a state of resilience? , 2011, Current Alzheimer research.

[98]  Arne Klungland,et al.  OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells , 2007, Nature.

[99]  W. Markesbery,et al.  Damage to lipids, proteins, DNA, and RNA in mild cognitive impairment. , 2007, Archives of neurology.

[100]  R. Nixon,et al.  The role of autophagy in neurodegenerative disease , 2013, Nature Medicine.

[101]  P. Sýkora,et al.  Modulation of DNA polymerase beta-dependent base excision repair in cultured human cells after low dose exposure to arsenite. , 2008, Toxicology and applied pharmacology.

[102]  D. C. Cabelof,et al.  Down syndrome as a model of DNA polymerase beta haploinsufficiency and accelerated aging , 2012, Mechanisms of Ageing and Development.

[103]  W. Markesbery,et al.  Identification and characterization of OGG1 mutations in patients with Alzheimer's disease , 2007, Nucleic acids research.

[104]  A. Verkhratsky,et al.  Impaired Adult Neurogenesis in the Dentate Gyrus of a Triple Transgenic Mouse Model of Alzheimer's Disease , 2008, PloS one.