Contributions of DNA Damage to Alzheimer’s Disease

International Journal of Molecular Sciences - Tập 21 Số 5 - Trang 1666
Xiaozeng Lin1,2,3,4, Anil Kapoor2,3,4, Yan Gu1,2,3,4, Mathilda Jing Chow1,2,3,4, Jingyi Peng1,2,3,4, Kuncheng Zhao1,2,3,4, Damu Tang1,2,3,4
1Department of Medicine, McMaster University, Hamilton, ON L8S 4K1, Canada
2Department of Surgery, McMaster University, Hamilton, ON L8S 4K1, Canada
3The Research Institute of St Joe's Hamilton, St Joseph's Hospital, Hamilton, ON L8N 4A6, Canada
4Urological Cancer Center for Research and Innovation (UCCRI), St Joseph's Hospital, Hamilton, ON L8N 4A6, Canada

Tóm tắt

Alzheimer’s disease (AD) is the most common type of neurodegenerative disease. Its typical pathology consists of extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles. Mutations in the APP, PSEN1, and PSEN2 genes increase Aβ production and aggregation, and thus cause early onset or familial AD. Even with this strong genetic evidence, recent studies support AD to result from complex etiological alterations. Among them, aging is the strongest risk factor for the vast majority of AD cases: Sporadic late onset AD (LOAD). Accumulation of DNA damage is a well-established aging factor. In this regard, a large amount of evidence reveals DNA damage as a critical pathological cause of AD. Clinically, DNA damage is accumulated in brains of AD patients. Genetically, defects in DNA damage repair resulted from mutations in the BRAC1 and other DNA damage repair genes occur in AD brain and facilitate the pathogenesis. Abnormalities in DNA damage repair can be used as diagnostic biomarkers for AD. In this review, we discuss the association, the causative potential, and the biomarker values of DNA damage in AD pathogenesis.

Từ khóa


Tài liệu tham khảo

Maurer, 1997, Auguste D and Alzheimer’s disease, Lancet, 349, 1546, 10.1016/S0140-6736(96)10203-8

Graeber, 1998, Histopathology and APOE genotype of the first Alzheimer disease patient, Auguste D, Neurogenetics, 1, 223, 10.1007/s100480050033

Graeber, 1999, Reanalysis of the first case of Alzheimer’s disease, Eur. Arch. Psychiatry Clin. Neurosci., 249, 10, 10.1007/PL00014167

Baumann, 1993, Abnormal Alzheimer-like phosphorylation of tau-protein by cyclin-dependent kinases cdk2 and cdk5, Febs Lett., 336, 417, 10.1016/0014-5793(93)80849-P

Wilkaniec, 2016, Cdk5 at crossroads of protein oligomerization in neurodegenerative diseases: Facts and hypotheses, J. Neurochem., 136, 222, 10.1111/jnc.13365

Kosik, 2014, Long- and short-term CDK5 knockdown prevents spatial memory dysfunction and tau pathology of triple transgenic Alzheimer’s mice, Front. Aging Neurosci., 6, 243

Kimura, 2013, Isomerase Pin1 stimulates dephosphorylation of tau protein at cyclin-dependent kinase (Cdk5)-dependent Alzheimer phosphorylation sites, J. Biol. Chem., 288, 7968, 10.1074/jbc.M112.433326

Cruz, 2003, Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles, Neuron, 40, 471, 10.1016/S0896-6273(03)00627-5

Teixeira, J.P., de Castro, A.A., Soares, F.V., da Cunha, E.F.F., and Ramalho, T.C. (2019). Future Therapeutic Perspectives into the Alzheimer’s Disease Targeting the Oxidative Stress Hypothesis. Molecules, 24.

Burdick, 1992, Assembly and aggregation properties of synthetic Alzheimer’s A4/beta amyloid peptide analogs, J. Biol. Chem., 267, 546, 10.1016/S0021-9258(18)48529-8

Gravina, 1995, Amyloid beta protein (A beta) in Alzheimer’s disease brain. Biochemical and immunocytochemical analysis with antibodies specific for forms ending at A beta 40 or A beta 42, J. Biol. Chem., 270, 7013, 10.1074/jbc.270.13.7013

Liu, 2017, Cdk5 links with DNA damage response and cancer, Mol. Cancer, 16, 60, 10.1186/s12943-017-0611-1

Huang, 2010, Cdk5: Links to DNA damage, Cell Cycle, 9, 3142, 10.4161/cc.9.16.12955

Madabhushi, 2014, DNA damage and its links to neurodegeneration, Neuron, 83, 266, 10.1016/j.neuron.2014.06.034

Vassar, 2004, BACE1: The beta-secretase enzyme in Alzheimer’s disease, J. Mol. Neurosci., 23, 105, 10.1385/JMN:23:1-2:105

Selkoe, 2007, Presenilin: Running with scissors in the membrane, Cell, 131, 215, 10.1016/j.cell.2007.10.012

Thinakaran, 2008, Amyloid precursor protein trafficking, processing, and function, J. Biol. Chem., 283, 29615, 10.1074/jbc.R800019200

Chow, 2010, Modeling an anti-amyloid combination therapy for Alzheimer’s disease, Sci. Transl. Med., 2, 13ra1, 10.1126/scitranslmed.3000337

Zhang, 2012, Proteolytic processing of Alzheimer’s beta-amyloid precursor protein, J. Neurochem., 120, 9, 10.1111/j.1471-4159.2011.07519.x

Bateman, 2011, Autosomal-dominant Alzheimer’s disease: A review and proposal for the prevention of Alzheimer’s disease, Alzheimer‘s Res. Ther., 3, 1

Snider, 2005, Novel presenilin 1 mutation (S170F) causing Alzheimer disease with Lewy bodies in the third decade of life, Arch. Neurol., 62, 1821, 10.1001/archneur.62.12.1821

Hardy, 1991, Amyloid deposition as the central event in the aetiology of Alzheimer’s disease, Trends Pharmacol. Sci., 12, 383, 10.1016/0165-6147(91)90609-V

Selkoe, 1991, The molecular pathology of Alzheimer’s disease, Neuron, 6, 487, 10.1016/0896-6273(91)90052-2

Hardy, 1992, Alzheimer’s disease: The amyloid cascade hypothesis, Science, 256, 184, 10.1126/science.1566067

Hardy, 2002, The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics, Science, 297, 353, 10.1126/science.1072994

Selkoe, 2016, The amyloid hypothesis of Alzheimer’s disease at 25 years, EMBO Mol. Med., 8, 595, 10.15252/emmm.201606210

Karran, 2016, The Cellular Phase of Alzheimer’s Disease, Cell, 164, 603, 10.1016/j.cell.2015.12.056

Lane, 2018, Alzheimer’s disease, Eur. J. Neurol., 25, 59, 10.1111/ene.13439

Migliore, 2009, Genetics, environmental factors and the emerging role of epigenetics in neurodegenerative diseases, Mutat. Res., 667, 82, 10.1016/j.mrfmmm.2008.10.011

Tse, 2017, Re-imagining Alzheimer’s disease—The diminishing importance of amyloid and a glimpse of what lies ahead, J. Neurochem., 143, 432, 10.1111/jnc.14079

Goldstein, 2020, Amyloid-beta-independent regulators of tau pathology in Alzheimer disease, Nat. Rev. Neurosci., 21, 21, 10.1038/s41583-019-0240-3

Coppede, 2015, DNA damage in neurodegenerative diseases, Mutat. Res., 776, 84, 10.1016/j.mrfmmm.2014.11.010

Masters, 2015, Alzheimer’s disease, Nat. Rev. Dis. Primers, 1, 15056, 10.1038/nrdp.2015.56

Caruso, 2019, Risk Factors for Alzheimer’s Disease: Focus on Stress, Front. Pharmacol., 10, 976, 10.3389/fphar.2019.00976

Riedel, 2016, Age, APOE and sex: Triad of risk of Alzheimer’s disease, J. Steroid Biochem. Mol. Biol., 160, 134, 10.1016/j.jsbmb.2016.03.012

Petr, M.A., Tulika, T., Carmona-Marin, L.M., and Scheibye-Knudsen, M. (2020). Protecting the Aging Genome. Trends Cell Biol., S0962–8924.

Hou, 2017, Genome instability in Alzheimer disease, Mech. Ageing Dev., 161, 83, 10.1016/j.mad.2016.04.005

Shamseer, 2015, Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: Elaboration and explanation, BMJ, 350, g7647, 10.1136/bmj.g7647

Moher, 2015, Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement, Syst. Rev., 4, 1, 10.1186/2046-4053-4-1

Dolle, 1997, Rapid accumulation of genome rearrangements in liver but not in brain of old mice, Nat. Genet., 17, 431, 10.1038/ng1297-431

Sedelnikova, 2004, Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks, Nat. Cell Biol., 6, 168, 10.1038/ncb1095

Lin, 2015, BMI1, ATM and DDR, Oncoscience, 2, 665, 10.18632/oncoscience.211

Myung, 2008, Evidence of DNA damage in Alzheimer disease: Phosphorylation of histone H2AX in astrocytes, Age, 30, 209, 10.1007/s11357-008-9050-7

Shanbhag, 2019, Early neuronal accumulation of DNA double strand breaks in Alzheimer’s disease, Acta Neuropathol. Commun., 7, 77, 10.1186/s40478-019-0723-5

Kirova, 2015, Working memory and executive function decline across normal aging, mild cognitive impairment, and Alzheimer’s disease, Biomed. Res. Int., 2015, 748212, 10.1155/2015/748212

Korolev, 2016, Alzheimer’s Disease Neuroimaging, I. Predicting Progression from Mild Cognitive Impairment to Alzheimer’s Dementia Using Clinical, MRI, and Plasma Biomarkers via Probabilistic Pattern Classification, PLoS ONE, 11, e0138866, 10.1371/journal.pone.0138866

Adamec, 1999, DNA strand breaks in Alzheimer’s disease, Brain Res., 849, 67, 10.1016/S0006-8993(99)02004-1

Canugovi, 2013, The role of DNA repair in brain related disease pathology, DNA Repair, 12, 578, 10.1016/j.dnarep.2013.04.010

Hegde, 2012, Oxidative genome damage and its repair: Implications in aging and neurodegenerative diseases, Mech. Ageing Dev., 133, 157, 10.1016/j.mad.2012.01.005

Shulman, 2004, Energetic basis of brain activity: Implications for neuroimaging, Trends Neurosci., 27, 489, 10.1016/j.tins.2004.06.005

Gabbita, 1998, Increased nuclear DNA oxidation in the brain in Alzheimer’s disease, J. Neurochem., 71, 2034, 10.1046/j.1471-4159.1998.71052034.x

Lyras, 1997, An assessment of oxidative damage to proteins, lipids, and DNA in brain from patients with Alzheimer’s disease, J. Neurochem., 68, 2061, 10.1046/j.1471-4159.1997.68052061.x

Lovell, 2007, Oxidative DNA damage in mild cognitive impairment and late-stage Alzheimer’s disease, Nucleic Acids Res., 35, 7497, 10.1093/nar/gkm821

Wang, 2006, Increased oxidative damage in nuclear and mitochondrial DNA in mild cognitive impairment, J. Neurochem., 96, 825, 10.1111/j.1471-4159.2005.03615.x

Timmons, 2014, Nucleic acid oxidation: An early feature of Alzheimer’s disease, J. Neurochem., 128, 294, 10.1111/jnc.12444

Lovell, 2011, Oxidatively modified nucleic acids in preclinical Alzheimer’s disease (PCAD) brain, Mech. Ageing Dev., 132, 443, 10.1016/j.mad.2011.08.003

Schmitt, 2000, “Preclinical” AD revisited: Neuropathology of cognitively normal older adults, Neurology, 55, 370, 10.1212/WNL.55.3.370

Lovell, 1999, Increased DNA oxidation and decreased levels of repair products in Alzheimer’s disease ventricular CSF, J. Neurochem., 72, 771, 10.1046/j.1471-4159.1999.0720771.x

Brasnjevic, 2008, Accumulation of nuclear DNA damage or neuron loss: Molecular basis for a new approach to understanding selective neuronal vulnerability in neurodegenerative diseases, DNA Repair, 7, 1087, 10.1016/j.dnarep.2008.03.010

Korr, 2001, Neuron loss during early adulthood following prenatal low-dose X-irradiation in the mouse brain, Int. J. Radiat. Biol., 77, 567, 10.1080/09553000010028467

Rutten, 2007, The aging brain: Accumulation of DNA damage or neuron loss?, Neurobiol. Aging, 28, 91, 10.1016/j.neurobiolaging.2005.10.019

McKinnon, 2017, Genome integrity and disease prevention in the nervous system, Genes Dev., 31, 1180, 10.1101/gad.301325.117

Suberbielle, 2013, Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-beta, Nat. Neurosci., 16, 613, 10.1038/nn.3356

Marnef, 2017, Transcription-Coupled DNA Double-Strand Break Repair: Active Genes Need Special Care, J. Mol. Biol., 429, 1277, 10.1016/j.jmb.2017.03.024

Madabhushi, 2015, Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes, Cell, 161, 1592, 10.1016/j.cell.2015.05.032

Crowe, 2006, Rapid phosphorylation of histone H2A.X following ionotropic glutamate receptor activation, Eur. J. Neurosci., 23, 2351, 10.1111/j.1460-9568.2006.04768.x

West, 2011, Neuronal activity-regulated gene transcription in synapse development and cognitive function, Cold Spring Harb. Perspect. Biol., 3, a005744, 10.1101/cshperspect.a005744

Bird, 2016, The Role of Epigenetic Mechanisms in the Regulation of Gene Expression in the Nervous System, J. Neurosci. Off. J. Soc. Neurosci., 36, 11427, 10.1523/JNEUROSCI.2492-16.2016

Ju, 2006, A topoisomerase IIbeta-mediated dsDNA break required for regulated transcription, Science, 312, 1798, 10.1126/science.1127196

Bunch, 2015, Transcriptional elongation requires DNA break-induced signalling, Nat. Commun., 6, 10191, 10.1038/ncomms10191

Haffner, 2010, Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements, Nat. Genet., 42, 668, 10.1038/ng.613

Williamson, 2011, Estrogen receptor alpha-mediated transcription induces cell cycle-dependent DNA double-strand breaks, Carcinogenesis, 32, 279, 10.1093/carcin/bgq255

Trotter, 2015, Glucocorticoid Receptor Transcriptional Activation via the BRG1-Dependent Recruitment of TOP2beta and Ku70/86, Mol. Cell. Biol., 35, 2799, 10.1128/MCB.00230-15

Austin, C.A., Lee, K.C., Swan, R.L., Khazeem, M.M., Manville, C.M., Cridland, P., Treumann, A., Porter, A., Morris, N.J., and Cowell, I.G. (2018). TOP2B: The First Thirty Years. Int. J. Mol. Sci., 19.

Harkin, 2016, Distinct expression patterns for type II topoisomerases IIA and IIB in the early foetal human telencephalon, J. Anat., 228, 452, 10.1111/joa.12416

King, 2013, Topoisomerases facilitate transcription of long genes linked to autism, Nature, 501, 58, 10.1038/nature12504

Gorbunova, 2016, DNA double strand break repair, aging and the chromatin connection, Mutat. Res., 788, 2, 10.1016/j.mrfmmm.2016.02.004

Su, 1997, Neuronal DNA damage precedes tangle formation and is associated with up-regulation of nitrotyrosine in Alzheimer’s disease brain, Brain Res., 774, 193, 10.1016/S0006-8993(97)81703-9

Sheng, 1998, Progressive neuronal DNA damage associated with neurofibrillary tangle formation in Alzheimer disease, J. Neuropathol. Exp. Neurol., 57, 323, 10.1097/00005072-199804000-00003

Ceccaldi, 2016, Repair Pathway Choices and Consequences at the Double-Strand Break, Trends Cell Biol., 26, 52, 10.1016/j.tcb.2015.07.009

Zhou, 2000, The DNA damage response: Putting checkpoints in perspective, Nature, 408, 433, 10.1038/35044005

Smith, 2010, The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer, Adv. Cancer Res., 108, 73, 10.1016/B978-0-12-380888-2.00003-0

Cassimere, E.K., Mauvais, C., and Denicourt, C. (2016). p27Kip1 Is Required to Mediate a G1 Cell Cycle Arrest Downstream of ATM following Genotoxic Stress. PLoS ONE, 11.

Lin, 2013, ERK kinases modulate the activation of PI3 kinase related kinases (PIKKs) in DNA damage response, Histol. Histopathol., 28, 1547

Jin, 2019, ATM in DNA repair in cancer, Pharmacol. Ther., 203, 107391, 10.1016/j.pharmthera.2019.07.002

Trenner, 2019, Harnessing DNA Double-Strand Break Repair for Cancer Treatment, Front. Oncol., 9, 1388, 10.3389/fonc.2019.01388

Biton, 2008, The neurological phenotype of ataxia-telangiectasia: Solving a persistent puzzle, DNA Repair, 7, 1028, 10.1016/j.dnarep.2008.03.006

Shen, 2016, Neurons in Vulnerable Regions of the Alzheimer’s Disease Brain Display Reduced ATM Signaling, eNeuro, 3, ENEURO.0124-15.2016, 10.1523/ENEURO.0124-15.2016

Wezyk, 2018, Overactive BRCA1 Affects Presenilin 1 in Induced Pluripotent Stem Cell-Derived Neurons in Alzheimer’s Disease, J. Alzheimer’s Dis. JAD, 62, 175, 10.3233/JAD-170830

Welty, 2018, RAD52 is required for RNA-templated recombination repair in post-mitotic neurons, J. Biol. Chem., 293, 1353, 10.1074/jbc.M117.808402

Yu, 2018, Altered DNA repair; an early pathogenic pathway in Alzheimer’s disease and obesity, Sci. Rep., 8, 5600, 10.1038/s41598-018-23644-4

Mano, 2017, Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer’s disease, Proc. Natl. Acad. Sci. USA, 114, E9645, 10.1073/pnas.1707151114

Nakamura, 2020, Aberrant Accumulation of BRCA1 in Alzheimer Disease and Other Tauopathies, J. Neuropathol. Exp. Neurol., 79, 22, 10.1093/jnen/nlz107

Guenette, 2006, Essential roles for the FE65 amyloid precursor protein-interacting proteins in brain development, EMBO J., 25, 420, 10.1038/sj.emboj.7600926

Kesavapany, 2002, Expression of the Fe65 adapter protein in adult and developing mouse brain, Neuroscience, 115, 951, 10.1016/S0306-4522(02)00422-0

Minopoli, 2012, Fe65 matters: New light on an old molecule, Iubmb Life, 64, 936, 10.1002/iub.1094

Ryu, 2015, An epigenomic role of Fe65 in the cellular response to DNA damage, Mutat. Res., 776, 40, 10.1016/j.mrfmmm.2015.01.006

Sun, 2005, A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM, Proc. Natl. Acad. Sci. USA, 102, 13182, 10.1073/pnas.0504211102

Sun, 2007, DNA damage-induced acetylation of lysine 3016 of ATM activates ATM kinase activity, Mol. Cell. Biol., 27, 8502, 10.1128/MCB.01382-07

Jowsey, 2015, Fe65 Ser228 is phosphorylated by ATM/ATR and inhibits Fe65-APP-mediated gene transcription, Biochem. J., 465, 413, 10.1042/BJ20140656

Langlands, H., Blain, P.G., and Jowsey, P.A. (2016). Fe65 Is Phosphorylated on Ser289 after UV-Induced DNA Damage. PLoS ONE, 11.

Itzhaki, 2008, Herpes simplex virus type 1 in Alzheimer’s disease: The enemy within, J. Alzheimer’s Dis. JAD, 13, 393, 10.3233/JAD-2008-13405

Ball, 2013, Intracerebral propagation of Alzheimer’s disease: Strengthening evidence of a herpes simplex virus etiology, Alzheimer’s Dement. J. Alzheimer’s Assoc., 9, 169, 10.1016/j.jalz.2012.07.005

Ezzat, 2019, The viral protein corona directs viral pathogenesis and amyloid aggregation, Nat. Commun., 10, 2331, 10.1038/s41467-019-10192-2

Racaniello, 2016, Herpes Simplex Virus-Type1 (HSV-1) Impairs DNA Repair in Cortical Neurons, Front. Aging Neurosci., 8, 242

Wei, 2013, Inhibition of ERK activation enhances the repair of double-stranded breaks via non-homologous end joining by increasing DNA-PKcs activation, Biochim. Biophys. Acta, 1833, 90, 10.1016/j.bbamcr.2012.10.016

Jette, 2015, The DNA-dependent protein kinase: A multifunctional protein kinase with roles in DNA double strand break repair and mitosis, Prog. Biophys. Mol. Biol., 117, 194, 10.1016/j.pbiomolbio.2014.12.003

Davydov, 2003, Is DNA repair compromised in Alzheimer’s disease?, Neurobiol. Aging, 24, 953, 10.1016/S0197-4580(02)00229-4

Simpson, 2010, Population variation in oxidative stress and astrocyte DNA damage in relation to Alzheimer-type pathology in the ageing brain, Neuropathol. Appl. Neurobiol., 36, 25, 10.1111/j.1365-2990.2009.01030.x

Culmsee, 2001, Hippocampal neurons of mice deficient in DNA-dependent protein kinase exhibit increased vulnerability to DNA damage, oxidative stress and excitotoxicity, Brain Res. Mol. Brain Res., 87, 257, 10.1016/S0169-328X(01)00008-0

Cardinale, 2012, Sublethal doses of beta-amyloid peptide abrogate DNA-dependent protein kinase activity, J. Biol. Chem., 287, 2618, 10.1074/jbc.M111.276550

Aguilera, 2016, Transcription-replication conflicts: How they occur and how they are resolved, Nat. Rev. Mol. Cell Biol., 17, 553, 10.1038/nrm.2016.88

Lindahl, 1993, Instability and decay of the primary structure of DNA, Nature, 362, 709, 10.1038/362709a0

Vilenchik, 2003, Endogenous DNA double-strand breaks: Production, fidelity of repair, and induction of cancer, Proc. Natl. Acad. Sci. USA, 100, 12871, 10.1073/pnas.2135498100

Hazra, 2007, Oxidative DNA damage repair in mammalian cells: A new perspective, DNA Repair, 6, 470, 10.1016/j.dnarep.2006.10.011

Wallace, 2014, Base excision repair: A critical player in many games, DNA Repair, 19, 14, 10.1016/j.dnarep.2014.03.030

Akbari, 2015, The role of DNA base excision repair in brain homeostasis and disease, DNA Repair, 32, 172, 10.1016/j.dnarep.2015.04.029

Lovell, 2000, Decreased base excision repair and increased helicase activity in Alzheimer’s disease brain, Brain Res., 855, 116, 10.1016/S0006-8993(99)02335-5

Weissman, 2007, Defective DNA base excision repair in brain from individuals with Alzheimer’s disease and amnestic mild cognitive impairment, Nucleic Acids Res., 35, 5545, 10.1093/nar/gkm605

Canugovi, 2014, Base excision DNA repair levels in mitochondrial lysates of Alzheimer’s disease, Neurobiol. Aging, 35, 1293, 10.1016/j.neurobiolaging.2014.01.004

Mao, 2007, Identification and characterization of OGG1 mutations in patients with Alzheimer’s disease, Nucleic Acids Res., 35, 2759, 10.1093/nar/gkm189

Jacob, 2013, Alzheimer’s disease-associated polymorphisms in human OGG1 alter catalytic activity and sensitize cells to DNA damage, Free Radic. Biol. Med., 63, 115, 10.1016/j.freeradbiomed.2013.05.010

Canugovi, 2012, Endonuclease VIII-like 1 (NEIL1) promotes short-term spatial memory retention and protects from ischemic stroke-induced brain dysfunction and death in mice, Proc. Natl. Acad. Sci. USA, 109, 14948, 10.1073/pnas.1204156109

Bandaru, 2002, A novel human DNA glycosylase that removes oxidative DNA damage and is homologous to Escherichia coli endonuclease VIII, DNA Repair, 1, 517, 10.1016/S1568-7864(02)00036-8

Hazra, 2002, Identification and characterization of a human DNA glycosylase for repair of modified bases in oxidatively damaged DNA, Proc. Natl. Acad. Sci. USA, 99, 3523, 10.1073/pnas.062053799

Hazra, 2002, Identification and characterization of a novel human DNA glycosylase for repair of cytosine-derived lesions, J. Biol. Chem., 277, 30417, 10.1074/jbc.C200355200

Takao, 2002, Novel nuclear and mitochondrial glycosylases revealed by disruption of the mouse Nth1 gene encoding an endonuclease III homolog for repair of thymine glycols, EMBO J., 21, 3486, 10.1093/emboj/cdf350

Englander, 2006, Differential modulation of base excision repair activities during brain ontogeny: Implications for repair of transcribed DNA, Mech. Ageing Dev., 127, 64, 10.1016/j.mad.2005.09.008

Love, 1999, Increased poly (ADP-ribosyl)ation of nuclear proteins in Alzheimer’s disease, Brain A J. Neurol., 122, 247, 10.1093/brain/122.2.247

Alano, 2010, NAD+ depletion is necessary and sufficient for poly (ADP-ribose) polymerase-1-mediated neuronal death, J. Neurosci. Off. J. Soc. Neurosci., 30, 2967, 10.1523/JNEUROSCI.5552-09.2010

Martire, 2016, Bioenergetic Impairment in Animal and Cellular Models of Alzheimer’s Disease: PARP-1 Inhibition Rescues Metabolic Dysfunctions, J. Alzheimer’s Dis. JAD, 54, 307, 10.3233/JAD-151040

Strosznajder, 2000, Effect of amyloid beta peptide on poly (ADP-ribose) polymerase activity in adult and aged rat hippocampus, Acta Biochim. Pol., 47, 847, 10.18388/abp.2000_4003

Strosznajder, 2012, Poly (ADP-ribose) polymerase-1 in amyloid beta toxicity and Alzheimer’s disease, Mol. Neurobiol., 46, 78, 10.1007/s12035-012-8258-9

Wu, 2014, NAD attenuates oxidative DNA damages induced by amyloid beta-peptide in primary rat cortical neurons, Free Radic. Res., 48, 794, 10.3109/10715762.2014.907889

Zeng, 2016, Nucleolar PARP-1 Expression Is Decreased in Alzheimer’s Disease: Consequences for Epigenetic Regulation of rDNA and Cognition, Neural Plast., 2016, 8987928, 10.1155/2016/8987928

Hou, 2018, NAD+ supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency, Proc. Natl. Acad. Sci. USA, 115, E1876, 10.1073/pnas.1718819115

Infante, 2007, Interaction between poly(ADP-ribose) polymerase 1 and interleukin 1A genes is associated with Alzheimer’s disease risk, Dement. Geriatr. Cogn. Disord., 23, 215, 10.1159/000099471

Liu, 2010, Evaluation of the poly(ADP-ribose) polymerase-1 gene variants in Alzheimer’s disease, J. Clin. Lab. Anal., 24, 182, 10.1002/jcla.20379

Cabelof, 2002, Attenuation of DNA polymerase beta-dependent base excision repair and increased DMS-induced mutagenicity in aged mice, Mutat. Res., 500, 135, 10.1016/S0027-5107(02)00003-9

Rao, 2001, DNA polymerase-beta may be the main player for defective DNA repair in aging rat neurons, Ann. N. Y. Acad. Sci., 928, 113, 10.1111/j.1749-6632.2001.tb05641.x

Ahmed, 2018, Loss of DNA polymerase beta induces cellular senescence, Environ. Mol. Mutagenes., 59, 603, 10.1002/em.22206

Athanasiou, 1980, Decreased repair of x-ray induced DNA single-strand breaks in lymphocytes in Down’s syndrome, Pediatr. Res., 4, 336, 10.1203/00006450-198004000-00015

Cabelof, 2009, Mutational spectrum at GATA1 provides insights into mutagenesis and leukemogenesis in Down syndrome, Blood, 114, 2753, 10.1182/blood-2008-11-190330

Esbensen, 2010, Health conditions associated with aging and end of life of adults with Down syndrome, Int. Rev. Res. Ment. Retard., 39, 107, 10.1016/S0074-7750(10)39004-5

Hartley, 2015, Down syndrome and Alzheimer’s disease: Common pathways, common goals, Alzheimer’s Dement. J. Alzheimer’s Assoc., 11, 700, 10.1016/j.jalz.2014.10.007

Mann, 1988, The pathological association between Down syndrome and Alzheimer disease, Mech. Ageing Dev., 43, 99, 10.1016/0047-6374(88)90041-3

Wisniewski, 1985, Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrome, Ann. Neurol., 17, 278, 10.1002/ana.410170310

Lai, 1989, A prospective study of Alzheimer disease in Down syndrome, Arch. Neurol., 46, 849, 10.1001/archneur.1989.00520440031017

Sykora, 2015, DNA polymerase beta deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes, Nucleic Acids Res., 43, 943, 10.1093/nar/gku1356

Misiak, 2017, DNA polymerase beta decrement triggers death of olfactory bulb cells and impairs olfaction in a mouse model of Alzheimer’s disease, Aging Cell, 16, 162, 10.1111/acel.12541

Hanagasi, 2007, The Arg194Trp polymorphism in DNA repair gene XRCC1 and the risk for sporadic late-onset Alzheimer’s disease, Neurol. Sci. Off. J. Ital. Neurol. Soc. Ital. Soc. Clin. Neurophysiol., 28, 31

Qian, 2010, Association of polymorphism of DNA repair gene XRCC1 with sporadic late-onset Alzheimer’s disease and age of onset in elderly Han Chinese, J. Neurol. Sci., 295, 62, 10.1016/j.jns.2010.05.002

Marcon, 2009, APE1/Ref-1 in Alzheimer’s disease: An immunohistochemical study, Neurosci. Lett., 466, 124, 10.1016/j.neulet.2009.09.039

Lillenes, 2016, Altered DNA base excision repair profile in brain tissue and blood in Alzheimer’s disease, Mol. Brain, 9, 61, 10.1186/s13041-016-0237-z

Lew, 1994, A brain-specific activator of cyclin-dependent kinase 5, Nature, 371, 423, 10.1038/371423a0

Tsai, 1994, p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5, Nature, 371, 419, 10.1038/371419a0

Tang, 1995, An isoform of the neuronal cyclin-dependent kinase 5 (Cdk5) activator, J. Biol. Chem., 270, 26897, 10.1074/jbc.270.45.26897

Sananbenesi, 2007, A hippocampal Cdk5 pathway regulates extinction of contextual fear, Nat. Neurosci., 10, 1012, 10.1038/nn1943

Liu, 2016, The Role of Cdk5 in Alzheimer’s Disease, Mol. Neurobiol., 53, 4328, 10.1007/s12035-015-9369-x

Su, 2011, Cyclin-dependent kinases in brain development and disease, Annu. Rev. Cell Dev. Biol., 27, 465, 10.1146/annurev-cellbio-092910-154023

Liu, 2003, Regulation of amyloid precursor protein (APP) phosphorylation and processing by p35/Cdk5 and p25/Cdk5, Febs Lett., 547, 193, 10.1016/S0014-5793(03)00714-2

Zheng, 2005, A Cdk5 inhibitory peptide reduces tau hyperphosphorylation and apoptosis in neurons, EMBO J., 24, 209, 10.1038/sj.emboj.7600441

Piedrahita, 2010, Silencing of CDK5 reduces neurofibrillary tangles in transgenic alzheimer’s mice, J. Neurosci. Off. J. Soc. Neurosci., 30, 13966, 10.1523/JNEUROSCI.3637-10.2010

Park, 2015, Loss of mitofusin 2 links beta-amyloid-mediated mitochondrial fragmentation and Cdk5-induced oxidative stress in neuron cells, J. Neurochem., 132, 687, 10.1111/jnc.12984

Weishaupt, 2003, Inhibition of CDK5 is protective in necrotic and apoptotic paradigms of neuronal cell death and prevents mitochondrial dysfunction, Mol. Cell. Neurosci., 24, 489, 10.1016/S1044-7431(03)00221-5

Kim, 2008, Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity, Neuron, 60, 803, 10.1016/j.neuron.2008.10.015

Mostafa, 2015, Herpes simplex virus 1 upregulates p35, alters CDK-5 localization, and stimulates CDK-5 kinase activity during acute infection in neurons, J. Virol., 89, 5171, 10.1128/JVI.00106-15

Tian, 2009, Phosphorylation of ATM by Cdk5 mediates DNA damage signalling and regulates neuronal death, Nat. Cell Biol., 11, 211, 10.1038/ncb1829

Robin, 2017, Calcium dysregulation and Cdk5-ATM pathway involved in a mouse model of fragile X-associated tremor/ataxia syndrome, Hum. Mol. Genet., 26, 2649, 10.1093/hmg/ddx148

Zheng, 2019, A mitotic CDK5-PP4 phospho-signaling cascade primes 53BP1 for DNA repair in G1, Nat. Commun., 10, 4252, 10.1038/s41467-019-12084-x

Huang, 2010, The role of Cdk5-mediated apurinic/apyrimidinic endonuclease 1 phosphorylation in neuronal death, Nat. Cell Biol., 12, 563, 10.1038/ncb2058

Zainuddin, 2018, Emerging Roles of Sirtuin 6 in Alzheimer’s Disease, J. Mol. Neurosci., 64, 157, 10.1007/s12031-017-1005-y

Khan, R.I., Nirzhor, S.S.R., and Akter, R. (2018). A Review of the Recent Advances Made with SIRT6 and its Implications on Aging Related Processes, Major Human Diseases, and Possible Therapeutic Targets. Biomolecules, 8.

Xiao, 2012, Progression of chronic liver inflammation and fibrosis driven by activation of c-JUN signaling in Sirt6 mutant mice, J. Biol. Chem., 287, 41903, 10.1074/jbc.M112.415182

Michishita, 2008, SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin, Nature, 452, 492, 10.1038/nature06736

Mostoslavsky, 2006, Genomic instability and aging-like phenotype in the absence of mammalian SIRT6, Cell, 124, 315, 10.1016/j.cell.2005.11.044

Kaidi, 2010, Human SIRT6 promotes DNA end resection through CtIP deacetylation, Science, 329, 1348, 10.1126/science.1192049

Mao, 2011, SIRT6 promotes DNA repair under stress by activating PARP1, Science, 332, 1443, 10.1126/science.1202723

Kaluski, 2017, Neuroprotective Functions for the Histone Deacetylase SIRT6, Cell Rep., 18, 3052, 10.1016/j.celrep.2017.03.008

Jung, 2016, p53-dependent SIRT6 expression protects Abeta42-induced DNA damage, Sci. Rep., 6, 25628, 10.1038/srep25628

Chua, 2019, miR-34a in Neurophysiology and Neuropathology, J. Mol. Neurosci., 67, 235, 10.1007/s12031-018-1231-y

Okun, E., Marton, D., Cohen, D., Griffioen, K., Kanfi, Y., Illouz, T., Madar, R., and Cohen, H.Y. (2017). Sirt6 alters adult hippocampal neurogenesis. PLoS ONE, 12.

Bacigaluppi, 2019, Endogenous neural precursor cells in health and disease, Brain Res., 1730, 146619, 10.1016/j.brainres.2019.146619

Kieron, 2019, Oxidative DNA Damage Signalling in Neural Stem Cells in Alzheimer’s Disease, Oxidative Med. Cell. Longev., 2019, 2149812, 10.1155/2019/2149812

Park, 2004, Bmi1, stem cells, and senescence regulation, J. Clin. Investig., 113, 175, 10.1172/JCI200420800

Park, 2003, Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells, Nature, 423, 302, 10.1038/nature01587

Molofsky, 2005, Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways, Genes Dev., 19, 1432, 10.1101/gad.1299505

Molofsky, 2003, Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation, Nature, 425, 962, 10.1038/nature02060

Bruggeman, 2005, Ink4a and Arf differentially affect cell proliferation and neural stem cell self-renewal in Bmi1-deficient mice, Genes Dev., 19, 1438, 10.1101/gad.1299305

Oguro, 2006, Differential impact of Ink4a and Arf on hematopoietic stem cells and their bone marrow microenvironment in Bmi1-deficient mice, J. Exp. Med., 203, 2247, 10.1084/jem.20052477

Rodilla, 2015, Bmi1 regulates murine intestinal stem cell proliferation and self-renewal downstream of Notch, Development, 142, 41, 10.1242/dev.107714

Sherr, 1998, Tumor surveillance via the ARF-p53 pathway, Genes Dev., 12, 2984, 10.1101/gad.12.19.2984

Robertson, 1999, Tissue-specific alternative splicing in the human INK4a/ARF cell cycle regulatory locus, Oncogene, 18, 3810, 10.1038/sj.onc.1202737

Ismail, 2010, BMI1-mediated histone ubiquitylation promotes DNA double-strand break repair, J. Cell Biol., 191, 45, 10.1083/jcb.201003034

Facchino, 2010, BMI1 confers radioresistance to normal and cancerous neural stem cells through recruitment of the DNA damage response machinery, J. Neurosci. Off. J. Soc. Neurosci., 30, 10096, 10.1523/JNEUROSCI.1634-10.2010

Chagraoui, 2011, An anticlastogenic function for the Polycomb Group gene Bmi1, Proc. Natl. Acad. Sci. USA, 108, 5284, 10.1073/pnas.1014263108

Lin, 2015, A Novel Aspect of Tumorigenesis-BMI1 Functions in Regulating DNA Damage Response, Biomolecules, 5, 3396, 10.3390/biom5043396

Chatoo, 2019, Heterochromatic genome instability and neurodegeneration sharing similarities with Alzheimer’s disease in old Bmi1+/− mice, Sci. Rep., 9, 594, 10.1038/s41598-018-37444-3

Flamier, 2018, Modeling Late-Onset Sporadic Alzheimer’s Disease through BMI1 Deficiency, Cell Rep., 23, 2653, 10.1016/j.celrep.2018.04.097

Aparicio, 2014, DNA double-strand break repair pathway choice and cancer, DNA Repair, 19, 169, 10.1016/j.dnarep.2014.03.014

Frade, 2015, Neuronal cell cycle: The neuron itself and its circumstances, Cell Cycle, 14, 712, 10.1080/15384101.2015.1004937

Lu, 2019, Amyloid-beta Oligomers-induced Mitochondrial DNA Repair Impairment Contributes to Altered Human Neural Stem Cell Differentiation, Curr. Alzheimer Res., 16, 934, 10.2174/1567205016666191023104036

Bernal, A., and Tusell, L. (2018). Telomeres: Implications for Cancer Development. Int. J. Mol. Sci., 19.

Ansari, 2019, Defective mitosis-linked DNA damage response and chromosomal instability in liver cancer, Biochim. Biophys. Acta. Rev. Cancer, 1872, 60, 10.1016/j.bbcan.2019.05.008

Jacobs, 2012, Detectable clonal mosaicism and its relationship to aging and cancer, Nat. Genet., 44, 651, 10.1038/ng.2270

Andriani, 2017, Mechanisms and consequences of aneuploidy and chromosome instability in the aging brain, Mech. Ageing Dev., 161 Pt A, 19, 10.1016/j.mad.2016.03.007

Yurov, 2019, Chromosome Instability in the Neurodegenerating Brain, Front. Genet., 10, 892, 10.3389/fgene.2019.00892

Yurov, 2014, X chromosome aneuploidy in the Alzheimer’s disease brain, Mol. Cytogenet., 7, 20, 10.1186/1755-8166-7-20

Oyama, 1994, Down’s syndrome: Up-regulation of beta-amyloid protein precursor and tau mRNAs and their defective coordination, J. Neurochem., 62, 1062, 10.1046/j.1471-4159.1994.62031062.x

Geller, 1999, Chromosome missegregation and trisomy 21 mosaicism in Alzheimer’s disease, Neurobiol. Dis., 6, 167, 10.1006/nbdi.1999.0236

Leandro, 2018, Changes in Expression Profiles Revealed by Transcriptomic Analysis in Peripheral Blood Mononuclear Cells of Alzheimer’s Disease Patients, J. Alzheimer’s Dis. JAD, 66, 1483, 10.3233/JAD-170205

Kwiatkowski, 2015, Variants of Base Excision Repair Genes MUTYH, PARP1 and XRCC1 in Alzheimer’s Disease Risk, Neuropsychobiology, 71, 176, 10.1159/000381985

Leandro, 2013, Lymphocytes of patients with Alzheimer’s disease display different DNA damage repair kinetics and expression profiles of DNA repair and stress response genes, Int. J. Mol. Sci., 14, 12380, 10.3390/ijms140612380

Siddiqui, 2018, gammaH2AX is increased in peripheral blood lymphocytes of Alzheimer’s disease patients in the South Australian Neurodegeneration, Nutrition and DNA Damage (SAND) study of aging, Mutat. Res. Genet. Toxicol. Environ. Mutagenes., 829, 6, 10.1016/j.mrgentox.2018.03.001

Francois, 2016, Guanine-quadruplexes are increased in mild cognitive impairment and correlate with cognitive function and chromosomal DNA damage, DNA Repair, 46, 29, 10.1016/j.dnarep.2016.08.001

Kwiatkowski, 2016, Associations between DNA Damage, DNA Base Excision Repair Gene Variability and Alzheimer’s Disease Risk, Dement. Geriatr. Cogn. Disord., 41, 152, 10.1159/000443953

Banda, 2017, Repair of 8-oxoG:A mismatches by the MUTYH glycosylase: Mechanism, metals and medicine, Free Radic. Biol. Med., 107, 202, 10.1016/j.freeradbiomed.2017.01.008

Sliwinska, 2016, The levels of 7,8-dihydrodeoxyguanosine (8-oxoG) and 8-oxoguanine DNA glycosylase 1 (OGG1)—A potential diagnostic biomarkers of Alzheimer’s disease, J. Neurol. Sci., 368, 155, 10.1016/j.jns.2016.07.008

Sliwinska, 2017, Decreased expression level of BER genes in Alzheimer’s disease patients is not derivative of their DNA methylation status, Prog. Neuro-Psychopharmacol. Biol. Psychiatry, 79, 311, 10.1016/j.pnpbp.2017.07.010

Moslemnezhad, 2016, Altered plasma marker of oxidative DNA damage and total antioxidant capacity in patients with Alzheimer’s disease, Casp. J. Intern. Med., 7, 88

Gao, 2019, POLD1 deficiency is involved in cognitive function impairment in AD patients and SAMP8 mice, Biomed. Pharmacother. Biomed. Pharmacother., 114, 108833, 10.1016/j.biopha.2019.108833

Coppede, 2017, Methylation analysis of DNA repair genes in Alzheimer’s disease, Mech. Ageing Dev., 161, 105, 10.1016/j.mad.2016.04.003

Tong, 2014, Brain metabolic dysfunction at the core of Alzheimer’s disease, Biochem. Pharmacol., 88, 548, 10.1016/j.bcp.2013.12.012

Mansuroglu, 2016, Loss of Tau protein affects the structure, transcription and repair of neuronal pericentromeric heterochromatin, Sci. Rep., 6, 33047, 10.1038/srep33047

Violet, 2014, A major role for Tau in neuronal DNA and RNA protection in vivo under physiological and hyperthermic conditions, Front. Cell. Neurosci., 8, 84, 10.3389/fncel.2014.00084

Lu, 2013, Hyperphosphorylation results in tau dysfunction in DNA folding and protection, J. Alzheimer’s Dis. JAD, 37, 551, 10.3233/JAD-130602

Frost, 2014, Tau promotes neurodegeneration through global chromatin relaxation, Nat. Neurosci., 17, 357, 10.1038/nn.3639

Tse, 2017, DNA damage in the oligodendrocyte lineage and its role in brain aging, Mech. Ageing Dev., 161, 37, 10.1016/j.mad.2016.05.006

Tse, 2018, DNA damage-associated oligodendrocyte degeneration precedes amyloid pathology and contributes to Alzheimer’s disease and dementia, Alzheimer’s Dement. J. Alzheimer’s Assoc., 14, 664, 10.1016/j.jalz.2017.11.010

Cahoy, 2008, A transcriptome database for astrocytes, neurons, and oligodendrocytes: A new resource for understanding brain development and function, J. Neurosci. Off. J. Soc. Neurosci., 28, 264, 10.1523/JNEUROSCI.4178-07.2008

Snaidero, 2014, Myelination at a glance, J. Cell Sci., 127, 2999, 10.1242/jcs.151043

Salami, 2003, Change of conduction velocity by regional myelination yields constant latency irrespective of distance between thalamus and cortex, Proc. Natl. Acad. Sci. USA, 100, 6174, 10.1073/pnas.0937380100

Butt, 2019, Oligodendroglial Cells in Alzheimer’s Disease, Adv. Exp. Med. Biol., 1175, 325, 10.1007/978-981-13-9913-8_12

Morell, 1980, Myelin, Sci. Am., 242, 88, 10.1038/scientificamerican0580-88

Bartzokis, 2001, Age-related changes in frontal and temporal lobe volumes in men: A magnetic resonance imaging study, Arch. Gen. Psychiatry, 58, 461, 10.1001/archpsyc.58.5.461

Bartzokis, 2003, White matter structural integrity in healthy aging adults and patients with Alzheimer disease: A magnetic resonance imaging study, Arch. Neurol., 60, 393, 10.1001/archneur.60.3.393

Coronel, 2019, Abeta42 Peptide Promotes Proliferation and Gliogenesis in Human Neural Stem Cells, Mol. Neurobiol., 56, 4023, 10.1007/s12035-018-1355-7

Silva, A.R., Santos, A.C., Farfel, J.M., Grinberg, L.T., Ferretti, R.E., Campos, A.H., Cunha, I.W., Begnami, M.D., Rocha, R.M., and Carraro, D.M. (2014). Repair of oxidative DNA damage, cell-cycle regulation and neuronal death may influence the clinical manifestation of Alzheimer’s disease. PLoS ONE, 9.

Suberbielle, 2015, DNA repair factor BRCA1 depletion occurs in Alzheimer brains and impairs cognitive function in mice, Nat. Commun., 6, 8897, 10.1038/ncomms9897