Critical role of mitosis in spontaneous late-onset Alzheimer’s disease; from a Shugoshin 1 cohesinopathy mouse model

References

• Jack CR Jr., Bennett DA, Blennow K, et al. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14:535–562.
   PubMed Web of Science ®Google Scholar
• Frisoni GB, Boccardi M, Barkhof F, et al. Strategic roadmap for an early diagnosis of Alzheimer’s disease based on biomarkers. Lancet Neurol. 2017;16:661–676.
   PubMed Web of Science ®Google Scholar
• Jansen WJ, Ossenkoppele R, Tijms BM, et al. Association of cerebral amyloid-β aggregation with cognitive functioning in persons without dementia. JAMA Psychiatry. 2018;75:84–95.
   PubMed Web of Science ®Google Scholar
• Jan AT, Azam M, Rahman S, et al. Perspective insights into disease progression, diagnostics, and therapeutic approaches in Alzheimer’s disease: a judicious update. Front Aging Neurosci. 2017;9:356.
   PubMed Web of Science ®Google Scholar
• Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;297:353–356.
   PubMed Web of Science ®Google Scholar
• Hardy J. The discovery of Alzheimer-causing mutations in the APP gene and the formulation of the “amyloid cascade hypothesis”. FEBS J. 2017;284:1040–1044.
   PubMed Web of Science ®Google Scholar
• Kametani F, Hasegawa M. Reconsideration of amyloid hypothesis and Tau hypothesis in Alzheimer’s disease. Front Neurosci. 2018;12:25.
   PubMed Web of Science ®Google Scholar
• Alzheimer’s organization [cited 2018 July 20]. Available from: https://www.alz.org/research/science/alzheimers_research.asp
   Google Scholar
• Scheltens P, Blennow K, Breteler MM, et al. Alzheimer’s disease. Lancet. 2016;388:505–517.
   PubMed Web of Science ®Google Scholar
• Cummings J, Aisen PS, DuBois B, et al. Drug development in Alzheimer’s disease: the path to 2025. Alzheimers Res Ther. 2016;8:39.
   PubMed Web of Science ®Google Scholar
• Qian X, Hamad B, Dias-Lalcaca G. The Alzheimer disease market. Nat Rev Drug Discov. 2015;14:675–676.
   PubMed Web of Science ®Google Scholar
• Cummings JL, Morstorf T, Zhong K. Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther. 2014;6:37.
   PubMed Web of Science ®Google Scholar
• Carroll J Another Alzheimer’s drug flops in pivotal clinical trial Endpoints News. cited 2017 Feb 15. Available from: http://www.sciencemag.org/news/2017/02/another-alzheimers-drug-flops-pivotal-clinical-trial
   Google Scholar
• Szeto JY, Lewis SJ. Current treatment options for Alzheimer’s disease and Parkinson’s disease dementia. Curr Neuropharmacol. 2016;14(4):326–338.
   PubMed Web of Science ®Google Scholar
• Logovinsky V, Satlin A, Lai R, et al. Safety and tolerability of BAN2401–a clinical study in Alzheimer’s disease with a protofibril selective Aβ antibody. Alzheimers Res Ther. 2016;8:14.
   PubMed Web of Science ®Google Scholar
• Söllvander S, Nikitidou E, Gallasch L, et al. The Aβ protofibril selective antibody mAb158 prevents accumulation of Aβ in astrocytes and rescues neurons from Aβ-induced cell death. J Neuroinflammation. 2018;15:98.
   PubMed Web of Science ®Google Scholar
• Hall AM, Roberson ED. Mouse models of Alzheimer’s disease. Brain Res Bull. 2012;88:3–12.
   PubMed Web of Science ®Google Scholar
• Sasaguri H, Nilsson P, Hashimoto S, et al. APP mouse models for Alzheimer’s disease preclinical studies. EMBO J. 2017;36:2473–2487.
   PubMed Web of Science ®Google Scholar
• Kitazawa M, Medeiros R, Laferla FM. Transgenic mouse models of Alzheimer disease: developing a better model as a tool for therapeutic interventions. Curr Pharm Des. 2012;18:1131–1147.
   PubMed Web of Science ®Google Scholar
• Ameen-Ali KE, Wharton SB, Simpson JE, et al. Review: neuropathology and behavioural features of transgenic murine models of Alzheimer’s disease. Neuropathol Appl Neurobiol. 2017;43:553–570.
   PubMed Web of Science ®Google Scholar
• Egan KJ, Vesterinen HM, Beglopoulos V, et al. From a mouse: systematic analysis reveals limitations of experiments testing interventions in Alzheimer’s disease mouse models. Evid Based Preclin Med. 2016;3:e00015.
   PubMedGoogle Scholar
• Wirths O. Altered neurogenesis in mouse models of Alzheimer disease. Neurogenesis (Austin). 2017;4:e1327002.
   PubMedGoogle Scholar
• Huang CC, Chung CM, Leu HB, et al. Diabetes mellitus and the risk of Alzheimer’s disease: a nationwide population-based study. PLoS One. 2014;9:e87095.
   PubMed Web of Science ®Google Scholar
• Hou Y, Song H, Croteau DL, et al. Genome instability in Alzheimer disease. Mech Ageing Dev. 2017;161:83–94.
   PubMed Web of Science ®Google Scholar
• Lee SL, Thomas P, Fenech M. Genome instability biomarkers and blood micronutrient risk profiles associated with mild cognitive impairment and Alzheimer’s disease. Mutat Res. 2015;776:54–83.
   PubMed Web of Science ®Google Scholar
• Hartley D, Blumenthal T, Carrillo M, et al. Down syndrome and Alzheimer’s disease: common pathways, common goals. Alzheimers Dement. 2015;11(6):700–709.
   PubMed Web of Science ®Google Scholar
• Chan GK, Jablonski SA, Sudakin V, et al. Human BUBR1 is a mitotic checkpoint kinase that monitors CENP-E functions at kinetochores and binds the cyclosome/APC. J Cell Biol. 1999;146:941–954.
   PubMed Web of Science ®Google Scholar
• Tang Z, Bharadwaj R, Li B, et al. Mad2-independent inhibition of APCCdc20 by the mitotic checkpoint protein BubR1. Dev Cell. 2001;1:227–237.
   PubMed Web of Science ®Google Scholar
• Kapanidou M, Lee S, Bolanos-Garcia VM. BubR1 kinase: protection against aneuploidy and premature aging. Trends Mol Med. 2015;21:364–372.
   PubMed Web of Science ®Google Scholar
• Dai W, Wang Q, Liu T, et al. Slippage of mitotic arrest and enhanced tumor development in mice with BubR1 haploinsufficiency. Cancer Res. 2004;64:440–445.
   PubMed Web of Science ®Google Scholar
• Rao CV, Yang YM, Swamy MV, et al. Colonic tumorigenesis in BubR1±ApcMin/+ compound mutant mice is linked to premature separation of sister chromatids and enhanced genomic instability. Proc Natl Acad Sci U S A. 2005;102(12):4365–4370.
   PubMed Web of Science ®Google Scholar
• Baker DJ, Jeganathan KB, Cameron JD, et al. BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nat Genet. 2004;36(7):744–749.
   PubMed Web of Science ®Google Scholar
• Baker DJ, Wijshake T, Tchkonia T, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011;479:232–236.
   PubMed Web of Science ®Google Scholar
• Baker DJ, Dawlaty MM, Wijshake T, et al. Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan. Nat Cell Biol. 2013;15:96–102.
   PubMed Web of Science ®Google Scholar
• Choi CI, Yoo KH, Hussaini SM, et al. The progeroid gene BubR1 regulates axon myelination and motor function. Aging (Albany NY). 2016;8:2667–2688.
   PubMedGoogle Scholar
• Yang Z, Jun H, Choi CI, et al. Age-related decline in BubR1 impairs adult hippocampal neurogenesis. Aging Cell. 2017;16:598–601.
   PubMed Web of Science ®Google Scholar
• Zivković L, Spremo-Potparević B, Djelić N, et al. Analysis of premature centromere division (PCD) of the chromosome 18 in peripheral blood lymphocytes in Alzheimer disease patients. Mech Ageing Dev. 2006;127:892–896.
   PubMed Web of Science ®Google Scholar
• Zivković L, Spremo-Potparević B, Plecas-Solarović B, et al. Premature centromere division of metaphase chromosomes in peripheral blood lymphocytes of Alzheimer’s disease patients: relation to gender and age. J Gerontol A Biol Sci Med Sci. 2010;65:1269–1274.
   PubMed Web of Science ®Google Scholar
• Bajic V, Spremo-Potparevic B, Zivkovic L, et al. Cohesion and the aneuploid phenotype in Alzheimer’s disease: a tale of genome instability. Neurosci Biobehav Rev. 2015;55:365–374.
   PubMed Web of Science ®Google Scholar
• Boveri T. Concerning the origin of malignant tumours by Theodor Boveri. Translated and annotated by Henry Harris. J Cell Sci. 2008;121(Suppl 1):1–84.
   PubMed Web of Science ®Google Scholar
• Schvartzman JM, Sotillo R, Benezra R. Mitotic chromosomal instability and cancer: mouse modelling of the human disease. Nat Rev Cancer. 2010;10(2):102–115.
   PubMed Web of Science ®Google Scholar
• Rao CV, Yamada HY, Yao Y, et al. Enhanced genomic instabilities caused by deregulated microtubule dynamics and chromosome segregation: a perspective from genetic studies in mice. Carcinogenesis. 2009;30:1469–1474.
   PubMed Web of Science ®Google Scholar
• Foijer F, Draviam VM, Sorger PK, et al. Studying chromosome instability in the mouse. Biochim Biophys Acta. 2008;1786:73–82.
   PubMed Web of Science ®Google Scholar
• Ricke RM, van Ree JH, van Deursen JM. Whole chromosome instability and cancer: a complex relationship. Trends Genet. 2008;24:457–466.
   PubMed Web of Science ®Google Scholar
• Rao CV, Yamada HY. Genomic instability and colon carcinogenesis: from the perspective of genes. Front Oncol. 2013;3:130.
   PubMedGoogle Scholar
• Weaver BA, Silk AD, Montagna C, et al. Aneuploidy acts both oncogenically and as a tumor suppressor. Cancer Cell. 2007;11:25–36.
   PubMed Web of Science ®Google Scholar
• Weaver BA, Cleveland DW. The role of aneuploidy in promoting and suppressing tumors. J Cell Biol. 2009;185:935–937.
   PubMed Web of Science ®Google Scholar
• Zasadil LM, Britigan EM, Ryan SD, et al. High rates of chromosome missegregation suppress tumor progression but do not inhibit tumor initiation. Mol Biol Cell. 2016;27:1981–1989.
   PubMed Web of Science ®Google Scholar
• Silk AD, Zasadil LM, Holland AJ, et al. Chromosome missegregation rate predicts whether aneuploidy will promote or suppress tumors. Proc Natl Acad Sci USA. 2013;110:E4134–41.
   PubMed Web of Science ®Google Scholar
• Funk LC, Zasadil LM, Weaver BA. Living in CIN: mitotic infidelity and its consequences for tumor promotion and suppression. Dev Cell. 2016;39:638–652.
   PubMed Web of Science ®Google Scholar
• Salic A, Waters JC, Mitchison TJ. Vertebrate shugoshin links sister centromere cohesion and kinetochore microtubule stability in mitosis. Cell. 2004;118:567–578.
   PubMed Web of Science ®Google Scholar
• McGuinness BE, Hirota T, Kudo NR, et al. Shugoshin prevents dissociation of cohesin from centromeres during mitosis in vertebrate cells. PLoS Biol. 2005;3:e86.
   PubMed Web of Science ®Google Scholar
• Schöckel L, Möckel M, Mayer B, et al. Cleavage of cohesin rings coordinates the separation of centrioles and chromatids. Nat Cell Biol. 2011;13:966–972.
   PubMed Web of Science ®Google Scholar
• Wang X, Yang Y, Duan Q, et al. sSgo1, a major splice variant of Sgo1, functions in centriole cohesion where it is regulated by Plk1. Dev Cell. 2008;14:331–341.
   PubMed Web of Science ®Google Scholar
• Tsang WY, Dynlacht BD. sSgo1, a guardian of centriole cohesion. Dev Cell. 2008;14:320–322.
   PubMed Web of Science ®Google Scholar
• Yamada HY, Yao Y, Wang X, et al. Haploinsufficiency of SGO1 results in deregulated centrosome dynamics, enhanced chromosomal instability and colon tumorigenesis. Cell Cycle. 2012;11:479–488.
   PubMed Web of Science ®Google Scholar
• Yamada HY, Zhang Y, Reddy A, et al. Tumor-promoting/progressing role of additional chromosome instability in hepatic carcinogenesis in Sgo1 (Shugoshin 1) haploinsufficient mice. Carcinogenesis. 2015;36:429–440.
   PubMed Web of Science ®Google Scholar
• Rao CV, Sanghera S, Zhang Y, et al. Antagonizing pathways leading to differential dynamics in colon carcinogenesis in Shugoshin1 (Sgo1)-haploinsufficient chromosome instability model. Mol Carcinog. 2016;55:600–610.
   PubMed Web of Science ®Google Scholar
• Iwaizumi M, Shinmura K, Mori H, et al. Human Sgo1 downregulation leads to chromosomal instability in colorectal cancer. Gut. 2009;58:249–260.
   PubMed Web of Science ®Google Scholar
• Kim MS, An CH, Yoo NJ, et al. Frameshift mutations of chromosome cohesion-related genes SGOL1 and PDS5B in gastric and colorectal cancers with high microsatellite instability. Hum Pathol. 2013;44:2234–2240.
   PubMed Web of Science ®Google Scholar
• Kahyo T, Iwaizumi M, Shinmura K, et al. A novel tumor-derived SGOL1 variant causes abnormal mitosis and unstable chromatid cohesion. Oncogene. 2011;30:4453–4463.
   PubMed Web of Science ®Google Scholar
• Matsuura S, Kahyo T, Shinmura K, et al. SGOL1 variant B induces abnormal mitosis and resistance to taxane in non-small cell lung cancers. Sci Rep. 2013;3:3012.
   PubMed Web of Science ®Google Scholar
• Wang LH, Yen CJ, Li TN, et al. Sgo1 is a potential therapeutic target for hepatocellular carcinoma. Oncotarget. 2015;6:2023–2033.
   PubMedGoogle Scholar
• Yamada HY, Kumar G, Zhang Y, et al. Systemic chromosome instability in Shugoshin-1 mice resulted in compromised glutathione pathway, activation of Wnt signaling and defects in immune system in the lung. Oncogenesis. 2016;5:e256.
   PubMed Web of Science ®Google Scholar
• Rao CV, Sanghera S, Zhang Y, et al. Systemic chromosome instability resulted in colonic transcriptomic changes in metabolic, proliferation, and stem cell regulators in Sgo1-/+ mice. Cancer Research. 2016;76:630–642.
   PubMed Web of Science ®Google Scholar
• Sheltzer JM, Torres EM, Dunham MJ, et al. Transcriptional consequences of aneuploidy. Proc Natl Acad Sci U S A. 2012;109:12644–12649.
   PubMed Web of Science ®Google Scholar
• Torres EM, Sokolsky T, Tucker CM, et al. Effects of aneuploidy on cellular physiology and cell division in haploid yeast. Science. 2007;317:916–924.
   PubMed Web of Science ®Google Scholar
• Williams BR, Prabhu VR, Hunter KE, et al. Aneuploidy affects proliferation and spontaneous immortalization in mammalian cells. Science. 2008;322:703–709.
   PubMed Web of Science ®Google Scholar
• Santaguida S, Vasile E, White E, et al. Aneuploidy-induced cellular stresses limit autophagic degradation. Genes Dev. 2015;29:2010–2021.
   PubMed Web of Science ®Google Scholar
• Chetaille P, Preuss C, Burkhard S, et al. Mutations in SGOL1 cause a novel cohesinopathy affecting heart and gut rhythm. Nat Genet. 2014;46(11):1245–1249.
   PubMed Web of Science ®Google Scholar
• Song AT, Galli A, Leclerc S, et al. Characterization of Sgo1 expression in developing and adult mouse. Gene Expr Patterns. 2017;25-26:36–45.
   PubMed Web of Science ®Google Scholar
• Song AT, Galli A, Leclerc S, et al. Dataset of Sgo1 expression in cardiac, gastrointestinal, hepatic and neuronal tissue in mouse. Data Brief. 2017;13:731–737.
   PubMed Web of Science ®Google Scholar
• Rao CV, Asch AS, Yamada HY. Emerging links among Chromosome Instability (CIN), cancer, and aging. Molecular Carcinogenesis. 2017;56:791–803.
   PubMed Web of Science ®Google Scholar
• Rao CV, Farooqui M, Zhang Y, et al. Spontaneous development of Alzheimer’s disease-associated brain pathology in a Shugoshin 1 mouse cohesinopathy model. Aging Cell. 2018;17(4):e12797. PMID: 29943428.
   PubMed Web of Science ®Google Scholar
• Valero J, Bernardino L, Cardoso FL, et al. Impact of neuroinflammation on hippocampal neurogenesis: relevance to aging and Alzheimer’s disease. J Alzheimers Dis. 2017;60:S161–S168.
   PubMed Web of Science ®Google Scholar
• Heneka MT, Carson MJ, El Khoury J, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14(4):388–405.
   PubMed Web of Science ®Google Scholar
• Sawikr Y, Yarla NS, Peluso I, et al. Neuroinflammation in Alzheimer’s disease: the preventive and therapeutic potential of polyphenolic nutraceuticals. Adv Protein Chem Struct Biol. 2017;108:33–57.
   PubMed Web of Science ®Google Scholar
• Praticò D. Oxidative stress hypothesis in Alzheimer’s disease: a reappraisal. Trends Pharmacol Sci. 2008;29:609–615.
   PubMed Web of Science ®Google Scholar
• Zhao Y, Zhao B. Oxidative stress and the pathogenesis of Alzheimer’s disease. Oxid Med Cell Longev. 2013;2013:316523.
   PubMed Web of Science ®Google Scholar
• García-Blanco A, Baquero M, Vento M, et al. Potential oxidative stress biomarkers of mild cognitive impairment due to Alzheimer disease. J Neurol Sci. 2017;373:295–302.
   PubMed Web of Science ®Google Scholar
• Connolly NMC, Theurey P, Adam-Vizi V, et al. Guidelines on experimental methods to assess mitochondrial dysfunction in cellular models of neurodegenerative diseases. Cell Death Differ. 2018;25:542–572.
   PubMed Web of Science ®Google Scholar
• Wang JM, Sun C. Calcium and neurogenesis in Alzheimer’s disease. Front Neurosci. 2010;4:194.
   PubMed Web of Science ®Google Scholar
• Leija-Salazar M, Piette C, Proukakis C. Review: somatic mutations in neurodegeneration. Neuropathol Appl Neurobiol. 2018;44(3):267–285.
   PubMed Web of Science ®Google Scholar
• Duncan T, Valenzuela M. Alzheimer’s disease, dementia, and stem cell therapy. Stem Cell Res Ther. 2017;8:111.
   PubMed Web of Science ®Google Scholar
• Schwartz M, Deczkowska A. Neurological disease as a failure of brain-immune crosstalk: the multiple faces of neuroinflammation. Trends Immunol. 2016;37:668–679.
   PubMed Web of Science ®Google Scholar
• Sweeney MD, Sagare AP, Zlokovic BV. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol. 2018;14:133–150.
   PubMed Web of Science ®Google Scholar
• Nalivaeva NN, Turner AJ. Role of ageing and oxidative stress in regulation of amyloid-degrading enzymes and development of neurodegeneration. Curr Aging Sci. 2017;10:32–40.
   PubMedGoogle Scholar
• Adlard PA, Tran BA, Finkelstein DI, et al. A review of β-amyloid neuroimaging in Alzheimer’s disease. Front Neurosci. 2014;8:327.
   PubMed Web of Science ®Google Scholar
• Avila J, Llorens-Martín M, Pallas-Bazarra N, et al. Cognitive decline in neuronal aging and Alzheimer’s disease: role of NMDA receptors and associated proteins. Front Neurosci. 2017;11:626.
   PubMed Web of Science ®Google Scholar
• Foster TC, Kyritsopoulos C, Kumar A. Central role for NMDA receptors in redox mediated impairment of synaptic function during aging and Alzheimer’s disease. Behav Brain Res. 2017;322:223–232.
   PubMed Web of Science ®Google Scholar
• Bredesen D. The end of Alzheimer’s: the first program to prevent and reverse cognitive decline. New York (NY): Avery; 2017. ISBN-10: 0735216207.
   Google Scholar
• Bredesen DE. Metabolic profiling distinguishes three subtypes of Alzheimer’s disease. Aging (Albany NY). 2015;7:595–600.
   PubMedGoogle Scholar
• Kondratick CM, Vandré DD. Alzheimer’s disease neurofibrillary tangles contain mitosis-specific phosphoepitopes. J Neurochem. 1996;67:2405–2416.
   PubMed Web of Science ®Google Scholar
• Delobel P, Flament S, Hamdane M, et al. Abnormal Tau phosphorylation of the Alzheimer-type also occurs during mitosis. J Neurochem. 2002;83:412–420.
   PubMed Web of Science ®Google Scholar
• Judge M, Hornbeck L, Potter H, et al. Mitosis-specific phosphorylation of amyloid precursor protein at threonine 668 leads to its altered processing and association with centrosomes. Mol Neurodegener. 2011;6:80.
   PubMed Web of Science ®Google Scholar
• Ogawa O, Zhu X, Lee HG, et al. Ectopic localization of phosphorylated histone H3 in Alzheimer’s disease: a mitotic catastrophe? Acta Neuropathol. 2003;105:524–528.
   PubMed Web of Science ®Google Scholar
• Folch J, Junyent F, Verdaguer E, et al. Role of cell cycle re-entry in neurons: a common apoptotic mechanism of neuronal cell death. Neurotox Res. 2012;22:195–207.
   PubMed Web of Science ®Google Scholar
• Yang Y, Herrup K. Cell division in the CNS: protective response or lethal event in post-mitotic neurons? Biochim Biophys Acta. 2007;1772:457–466.
   PubMed Web of Science ®Google Scholar
• Zhu X, Lee HG, Perry G, et al. Alzheimer disease, the two-hit hypothesis: an update. Biochim Biophys Acta. 2007;1772:494–502.
   PubMed Web of Science ®Google Scholar
• Zhu X, Raina AK, Perry G, et al. Alzheimer’s disease: the two-hit hypothesis. Lancet Neurol. 2004;3:219–226.
   PubMed Web of Science ®Google Scholar
• Webber KM, Raina AK, Marlatt MW, et al. The cell cycle in Alzheimer disease: a unique target for neuropharmacology. Mech Ageing Dev. 2005;126:1019–1025.
   PubMed Web of Science ®Google Scholar
• Vincent I, Bu B, Hudson K, et al. Constitutive Cdc25B tyrosine phosphatase activity in adult brain neurons with M phase-type alterations in Alzheimer disease. Neuroscience. 2001;105:639–650.
   PubMed Web of Science ®Google Scholar
• Ding XL, Husseman J, Tomashevski A, et al. The cell cycle Cdc25A tyrosine phosphatase is activated in degenerating postmitotic neurons in Alzheimer disease. Am J Pathol. 2000;157:1983–1990.
   PubMed Web of Science ®Google Scholar
• Tomashevski A, Husseman J, Jin LW, et al. Constitutive Wee1 activity in adult brain neurons with M phase-type alterations in Alzheimer neurodegeneration. J Alzheimers Dis. 2001;3:195–207.
   PubMed Web of Science ®Google Scholar
• Seward ME, Swanson E, Norambuena A, et al. Amyloid-β signals through tau to drive ectopic neuronal cell cycle re-entry in Alzheimer’s disease. J Cell Sci. 2013;126:1278–1286.
   PubMed Web of Science ®Google Scholar
• Csiszar A, Tarantini S, Fülöp GA, et al. Hypertension impairs neurovascular coupling and promotes microvascular injury: role in exacerbation of Alzheimer’s disease. Geroscience. 2017. PMID: 28853030.
   Web of Science ®Google Scholar
• Tucsek Z, Noa Valcarcel-Ares M, Tarantini S, et al. Hypertension-induced synapse loss and impairment in synaptic plasticity in the mouse hippocampus mimics the aging phenotype: implications for the pathogenesis of vascular cognitive impairment. Geroscience. 2017. PMID: 28664509.
   PubMed Web of Science ®Google Scholar
• Orehek AJ. The micron stroke hypothesis of Alzheimer’s disease and dementia. Med Hypotheses. 2012;78:562–570.
   PubMed Web of Science ®Google Scholar
• Shi S, Liang D, Chen Y, et al. Gx-50 reduces β-amyloid-induced TNF-α, IL-1β, NO, and PGE2 expression and inhibits NF-κB signaling in a mouse model of Alzheimer’s disease. Eur J Immunol. 2016;46(3):665–676.
   PubMed Web of Science ®Google Scholar
• Li X, Long J, He T, et al. Integrated genomic approaches identify major pathways and upstream regulators in late onset Alzheimer’s disease. Sci Rep. 2015;5:12393.
   PubMed Web of Science ®Google Scholar
• Arendt T, Holzer M, Stöbe A, et al. Activated mitogenic signaling induces a process of dedifferentiation in Alzheimer’s disease that eventually results in cell death. Ann N Y Acad Sci. 2000;920:249–255.
   PubMed Web of Science ®Google Scholar
• Yang Y, Wang X, Dai W. Human Sgo1 is an excellent target for induction of apoptosis of transformed cells. Cell Cycle. 2006;5:896–901.
   PubMed Web of Science ®Google Scholar
• Bordiuk OL, Smith K, Morin PJ, et al. Cell proliferation and neurogenesis in adult mouse brain. PLoS One. 2014;9:e111453.
   PubMed Web of Science ®Google Scholar
• Wang W, Bu B, Xie M, et al. Neural cell cycle dysregulation and central nervous system diseases. Prog Neurobiol. 2009;89:1–17.
   PubMed Web of Science ®Google Scholar
• Rosenkrantz JL, Carbone L. Investigating somatic aneuploidy in the brain: why we need a new model. Chromosoma. 2017;126:337–350.
   PubMed Web of Science ®Google Scholar
• Kline AD, Krantz ID, Deardorff MA, et al. Cornelia de Lange syndrome and molecular implications of the cohesin complex: abstracts from the 7th biennial scientific and educational symposium 2016. Am J Med Genet A. 2017;173:1172–1185.
   PubMed Web of Science ®Google Scholar
• Kumar R, Corbett MA, Van Bon BW, et al. Increased STAG2 dosage defines a novel cohesinopathy with intellectual disability and behavioral problems. Hum Mol Genet. 2015;24:7171–7181.
   PubMed Web of Science ®Google Scholar
• Nigg EA, Čajánek L, Arquint C. The centrosome duplication cycle in health and disease. FEBS Lett. 2014;588:2366–2372.
   PubMed Web of Science ®Google Scholar
• Bajić VP, Spremo-Potparević B, Zivković L, et al. Is the time dimension of the cell cycle re-entry in AD regulated by centromere cohesion dynamics? Biosci Hypotheses. 2008;1:156–161.
   PubMedGoogle Scholar
• Van Dam D, De Deyn PP. Non human primate models for Alzheimer’s disease-related research and drug discovery. Expert Opin Drug Discov. 2017;12(2):187–200.
   PubMed Web of Science ®Google Scholar
• Chikara S, Nagaprashantha LD, Singhal J, et al. Oxidative stress and dietary phytochemicals: role in cancer chemoprevention and treatment. Cancer Lett. 2018;413:122–134.
   PubMed Web of Science ®Google Scholar
• Wilson DW, Nash P, Buttar HS, et al. The role of food antioxidants, benefits of functional foods, and influence of feeding habits on the health of the older person: an overview. Antioxidants (Basel). 2017;6:E81.
   PubMedGoogle Scholar
• Rao CV, Pal S, Mohammed A, et al. Biological effects and epidemiological consequences of arsenic exposure, and reagents that can ameliorate arsenic damage in vivo. Oncotarget. 2017;8:57605–57621.
   PubMedGoogle Scholar
• O’Leary B, Finn RS, Turner NC. Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol. 2016;13:417–430.
   PubMed Web of Science ®Google Scholar
• Salmela AL, Kallio MJ. Mitosis as an anti-cancer drug target. Chromosoma. 2013;122:431–449.
   PubMed Web of Science ®Google Scholar
• Rao CV, Kurkjian CD, Yamada HY. Mitosis-targeting natural products for cancer prevention and therapy. Curr Drug Targets. 2012;13:1820–1830.
   PubMed Web of Science ®Google Scholar
• Motwani M, Li X, Schwartz GK. Flavopiridol, a cyclin-dependent kinase inhibitor, prevents spindle inhibitor-induced endoreduplication in human cancer cells. Clin Cancer Res. 2000;6:924–932.
   PubMed Web of Science ®Google Scholar
• Srikumar T, Padmanabhan J. Potential use of flavopiridol in treatment of chronic diseases. Adv Exp Med Biol. 2016;929:209–228.
   PubMedGoogle Scholar
• Zeidner JF, Karp JE. Clinical activity of alvocidib (flavopiridol) in acute myeloid leukemia. Leuk Res. 2015;39(12):1312–1318.
   PubMed Web of Science ®Google Scholar
• Jorda EG, Verdaguer E, Canudas AM, et al. Neuroprotective action of flavopiridol, a cyclin-dependent kinase inhibitor, in colchicine-induced apoptosis. Neuropharmacology. 2003;45:672–683.
   PubMed Web of Science ®Google Scholar
• Leggio GM, Catania MV, Puzzo D, et al. The antineoplastic drug flavopiridol reverses memory impairment induced by Amyloid-ß1-42 oligomers in mice. Pharmacol Res. 2016;106:10–20.
   PubMed Web of Science ®Google Scholar
• Kodaira H, Kusuhara H, Ushiki J, et al. Kinetic analysis of the cooperation of P-glycoprotein (P-gp/Abcb1) and breast cancer resistance protein (Bcrp/Abcg2) in limiting the brain and testis penetration of erlotinib, flavopiridol, and mitoxantrone. J Pharmacol Exp Ther. 2010;333:788–796.
   PubMed Web of Science ®Google Scholar
• Wadman M. NIH gambles on recycled drugs. Nature. 2013;499:263–264.
   PubMed Web of Science ®Google Scholar
• National NIH Center for Advancing Translational Science [cited 2018 July 20]. Available from: https://ncats.nih.gov/preclinical/repurpose
   Google Scholar
• Kaufman AC, Salazar SV, Haas LT, et al. Fyn inhibition rescues established memory and synapse loss in Alzheimer mice. Ann Neurol. 2015;77:953–971.
   PubMed Web of Science ®Google Scholar
• Folch J, Petrov D, Ettcheto M, et al. Current research therapeutic strategies for Alzheimer’s disease treatment. Neural Plast. 2016;2016:8501693.
   PubMed Web of Science ®Google Scholar