1932

Abstract

Those with Down syndrome (DS)—trisomy for chromosome 21—are routinely impacted by cognitive dysfunction and behavioral challenges in children and adults and Alzheimer's disease in older adults. No proven treatments specifically address these cognitive or behavioral changes. However, advances in the establishment of rodent models and human cell models promise to support development of such treatments. A research agenda that emphasizes the identification of overexpressed genes that contribute demonstrably to abnormalities in cognition and behavior in model systems constitutes a rational next step. Normalizing expression of such genes may usher in an era of successful treatments applicable across the life span for those with DS.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-041521-103641
2022-01-06
2024-06-18
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/62/1/annurev-pharmtox-041521-103641.html?itemId=/content/journals/10.1146/annurev-pharmtox-041521-103641&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Down JLH. 1995. 1866. Observations on an ethnic classification of idiots. Ment. Retard. 33:54–56
    [Google Scholar]
  2. 2. 
    Lejeune J, Gauthier M, Turpin R. 1959. Les chromosomes humains en culture de tissus [Human chromosomes in tissue cultures]. C. R. Hebd. Seances Acad. Sci. 248:602–3
    [Google Scholar]
  3. 3. 
    Gautier M. 2009. Cinquantenaire de la trisomie 21: retour sur une découverte [Fiftieth anniversary of the trisomy 21: return on a discovery]. Med. Sci. 25:311–15
    [Google Scholar]
  4. 4. 
    Allen G, Benda CE, Book JA, Carter CO, Ford CE et al. 1961. Mongolism. Am. J. Hum. Genet. 13:426
    [Google Scholar]
  5. 5. 
    de Graaf G, Buckley F, Skotko BG. 2015. Estimates of the live births, natural losses, and elective terminations with Down syndrome in the United States. Am. J. Med. Genet. A 167A:756–67
    [Google Scholar]
  6. 6. 
    Antonarakis SE, Skotko BG, Rafii MS, Strydom A, Pape SE et al. 2020. Down syndrome. Nat. Rev. Dis. Primers 6:9
    [Google Scholar]
  7. 7. 
    Bull MJ. 2020. Down syndrome. N. Engl. J. Med. 382:2344–52
    [Google Scholar]
  8. 8. 
    Zigman WB. 2013. Atypical aging in Down syndrome. Dev. Disabil. Res. Rev. 18:51–67
    [Google Scholar]
  9. 9. 
    Ballard C, Mobley W, Hardy J, Williams G, Corbett A 2016. Dementia in Down's syndrome. Lancet Neurol 15:622–36
    [Google Scholar]
  10. 10. 
    Lott IT, Head E. 2019. Dementia in Down syndrome: unique insights for Alzheimer disease research. Nat. Rev. Neurol. 15:135–47
    [Google Scholar]
  11. 11. 
    Bayen E, Possin KL, Chen Y, de Langavant LC, Yaffe K. 2018. Prevalence of aging, dementia, and multimorbidity in older adults with Down syndrome. JAMA Neurol 75:1399–406
    [Google Scholar]
  12. 12. 
    Englund A, Jonsson B, Zander CS, Gustafsson J, Annerén G 2013. Changes in mortality and causes of death in the Swedish Down syndrome population. Am. J. Med. Genet. A 161A:642–49
    [Google Scholar]
  13. 13. 
    Yang Q, Rasmussen SA, Friedman JM. 2002. Mortality associated with Down's syndrome in the USA from 1983 to 1997: a population-based study. Lancet 359:1019–25
    [Google Scholar]
  14. 14. 
    Wiseman FK, Al-Janabi T, Hardy J, Karmiloff-Smith A, Nizetic D et al. 2015. A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome. Nat. Rev. Neurosci. 16:564–74
    [Google Scholar]
  15. 15. 
    Bartesaghi R, Guidi S, Ciani E 2011. Is it possible to improve neurodevelopmental abnormalities in Down syndrome?. Rev. Neurosci. 22:419–55
    [Google Scholar]
  16. 16. 
    Stagni F, Giacomini A, Emili M, Guidi S, Bartesaghi R 2018. Neurogenesis impairment: an early developmental defect in Down syndrome. Free Radic. Biol. Med. 114:15–32
    [Google Scholar]
  17. 17. 
    Noctor SC, Martínez-Cerdeño V, Ivic L, Kriegstein AR 2004. Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat. Neurosci. 7:136–44
    [Google Scholar]
  18. 18. 
    Marin O. 2013. Cellular and molecular mechanisms controlling the migration of neocortical interneurons. Eur. J. Neurosci. 38:2019–29
    [Google Scholar]
  19. 19. 
    Hibaoui Y, Grad I, Letourneau A, Sailani MR, Dahoun S et al. 2014. Modelling and rescuing neurodevelopmental defect of Down syndrome using induced pluripotent stem cells from monozygotic twins discordant for trisomy 21. EMBO Mol. Med. 6:259–77
    [Google Scholar]
  20. 20. 
    Sobol M, Klar J, Laan L, Shahsavani M, Schuster J et al. 2019. Transcriptome and proteome profiling of neural induced pluripotent stem cells from individuals with Down syndrome disclose dynamic dysregulations of key pathways and cellular functions. Mol. Neurobiol. 56:7113–27
    [Google Scholar]
  21. 21. 
    Xu R, Brawner AT, Li S, Liu J, Kim H et al. 2019. OLIG2 drives abnormal neurodevelopmental phenotypes in human iPSC-based organoid and chimeric mouse models of Down syndrome. bioRxiv 462739. https://doi.org/10.1101/462739
    [Crossref]
  22. 22. 
    Chakrabarti L, Best TK, Cramer NP, Carney RSE, Isaac JTR et al. 2010. Olig1 and Olig2 triplication causes developmental brain defects in Down syndrome. Nat. Neurosci. 13:927–34
    [Google Scholar]
  23. 23. 
    Stagni F, Giacomini A, Emili M, Uguagliati B, Bonasoni MP et al. 2020. Neuroanatomical alterations in higher-order thalamic nuclei of fetuses with Down syndrome. Clin. Neurol. Neurosurg. 194:105870
    [Google Scholar]
  24. 24. 
    Guidi S, Bonasoni P, Ceccarelli C, Santini D, Gualtieri F et al. 2008. Neurogenesis impairment and increased cell death reduce total neuron number in the hippocampal region of fetuses with Down syndrome. Brain Pathol 18:180–97
    [Google Scholar]
  25. 25. 
    Lu J, Lian G, Zhou H, Esposito G, Steardo L et al. 2012. OLIG2 over-expression impairs proliferation of human Down syndrome neural progenitors. Hum. Mol. Genet. 21:2330–40
    [Google Scholar]
  26. 26. 
    Lu HE, Yang YC, Chen SM, Su HL, Huang PC et al. 2013. Modeling neurogenesis impairment in Down syndrome with induced pluripotent stem cells from Trisomy 21 amniotic fluid cells. Exp. Cell Res. 319:498–505
    [Google Scholar]
  27. 27. 
    Bahn S, Mimmack M, Ryan M, Caldwell MA, Jauniaux E et al. 2002. Neuronal target genes of the neuron-restrictive silencer factor in neurospheres derived from fetuses with Down's syndrome: a gene expression study. Lancet 359:310–15
    [Google Scholar]
  28. 28. 
    Chen C, Jiang P, Xue H, Peterson SE, Tran HT et al. 2014. Role of astroglia in Down's syndrome revealed by patient-derived human-induced pluripotent stem cells. Nat. Commun. 5:4430
    [Google Scholar]
  29. 29. 
    Bhattacharyya A, McMillan E, Chen SI, Wallace K, Svendsen CN 2009. A critical period in cortical interneuron neurogenesis in Down syndrome revealed by human neural progenitor cells. Dev. Neurosci. 31:497–510
    [Google Scholar]
  30. 30. 
    Guidi S, Giacomini A, Stagni F, Emili M, Uguagliati B et al. 2018. Abnormal development of the inferior temporal region in fetuses with Down syndrome. Brain Pathol 28:986–98
    [Google Scholar]
  31. 31. 
    Huo H-Q, Qu Z-Y, Yuan F, Ma L, Yao L et al. 2018. Modeling Down syndrome with patient iPSCs reveals cellular and migration deficits of GABAergic neurons. Stem Cell Rep 10:1251–66
    [Google Scholar]
  32. 32. 
    Takashima S, Becker LE, Armstrong DL, Chan F 1981. Abnormal neuronal development in the visual cortex of the human fetus and infant with Down's syndrome: a quantitative and qualitative Golgi study. Brain Res 225:1–21
    [Google Scholar]
  33. 33. 
    Becker LE, Armstrong DL, Chan F 1986. Dendritic atrophy in children with Down's syndrome. Ann. Neurol. 20:520–26
    [Google Scholar]
  34. 34. 
    Abraham H, Vincze A, Veszpremi B, Kravjak A, Gomori E et al. 2011. Impaired myelination of the human hippocampal formation in Down syndrome. Int. J. Dev. Neurosci. 30:147–58
    [Google Scholar]
  35. 35. 
    Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S et al. 2019. Single-cell transcriptomic analysis of Alzheimer's disease. Nature 570:332–37
    [Google Scholar]
  36. 36. 
    Tarui T, Im K, Madan N, Madankumar R, Skotko BG et al. 2020. Quantitative MRI analyses of regional brain growth in living fetuses with Down syndrome. Cereb. Cortex 30:382–90
    [Google Scholar]
  37. 37. 
    Herault Y, Delabar JM, Fisher EMC, Tybulewicz VLJ, Yu E, Brault V 2017. Rodent models in Down syndrome research: impact and future opportunities. Dis. Model. Mech. 10:1165–86
    [Google Scholar]
  38. 38. 
    Kazuki Y, Gao FJ, Li Y, Moyer AJ, Devenney B et al. 2020. A non-mosaic transchromosomic mouse model of Down syndrome carrying the long arm of human chromosome 21. eLife 9:e56223
    [Google Scholar]
  39. 39. 
    Costa ACS, Scott-McKean JJ. 2013. Prospects for improving brain function in individuals with Down syndrome. CNS Drugs 27:679–702
    [Google Scholar]
  40. 40. 
    Stagni F, Giacomini A, Guidi S, Ciani E, Bartesaghi R 2015. Timing of therapies for Down syndrome: the sooner, the better. Front. Behav. Neurosci. 9:265
    [Google Scholar]
  41. 41. 
    Gardiner KJ. 2015. Pharmacological approaches to improving cognitive function in Down syndrome: current status and considerations. Drug Des. Dev. Ther. 9:103–25
    [Google Scholar]
  42. 42. 
    Rueda N, Flórez J, Dierssen M, Martínez-Cué C. 2020. Translational validity and implications of pharmacotherapies in preclinical models of Down syndrome. Prog. Brain Res. 251:245–68
    [Google Scholar]
  43. 43. 
    Vacca RA, Bawari S, Valenti D, Tewari D, Nabavi SF et al. 2019. Down syndrome: neurobiological alterations and therapeutic targets. Neurosci. Biobehav. Rev. 98:234–55
    [Google Scholar]
  44. 44. 
    Hart SJ, Visootsak J, Tamburri P, Phuong P, Baumer N et al. 2017. Pharmacological interventions to improve cognition and adaptive functioning in Down syndrome: strides to date. Am. J. Med. Genet. A 173:3029–41
    [Google Scholar]
  45. 45. 
    Nakano-Kobayashi A, Awaya T, Kii I, Sumida Y, Okuno Y et al. 2017. Prenatal neurogenesis induction therapy normalizes brain structure and function in Down syndrome mice. PNAS 114:10268–73
    [Google Scholar]
  46. 46. 
    Stagni F, Uguagliati B, Emili M, Giacomini A, Bartesaghi R, Guidi S. 2021. The flavonoid 7,8-DHF fosters prenatal brain proliferation potency in a mouse model of Down syndrome. Sci. Rep. 11:6300
    [Google Scholar]
  47. 47. 
    Gough G, O'Brien NL, Alic I, Goh PA, Yeap YJ et al. 2020. Modeling Down syndrome in cells: from stem cells to organoids. Prog. Brain Res. 251:55–90
    [Google Scholar]
  48. 48. 
    Lu J, Esposito G, Scuderi C, Steardo L, Delli-Bovi LC et al. 2011. S100B and APP promote a gliocentric shift and impaired neurogenesis in Down syndrome neural progenitors. PLOS ONE 6:e22126
    [Google Scholar]
  49. 49. 
    Enright HA, Lam D, Sebastian A, Sales AP, Cadena J et al. 2020. Functional and transcriptional characterization of complex neuronal co-cultures. Sci. Rep. 10:11007
    [Google Scholar]
  50. 50. 
    Tambalo M, Lodato S. 2020. Brain organoids: human 3D models to investigate neuronal circuits assembly, function and dysfunction. Brain Res 1746:147028
    [Google Scholar]
  51. 51. 
    Papaspyropoulos A, Tsolaki M, Foroglou N, Pantazaki AA. 2020. Modeling and targeting Alzheimer's disease with organoids. Front. Pharmacol. 11:396
    [Google Scholar]
  52. 52. 
    Real R, Peter M, Trabalza A, Khan S, Smith MA et al. 2018. In vivo modeling of human neuron dynamics and Down syndrome. Science 362:eaau1810
    [Google Scholar]
  53. 53. 
    Czermiński JT, Lawrence JB. 2020. Silencing trisomy 21 with XIST in neural stem cells promotes neuronal differentiation. Dev. Cell 52:294–308.e3
    [Google Scholar]
  54. 54. 
    Kurabayashi N, Nguyen MD, Sanada K. 2019. Triple play of DYRK1A kinase in cortical progenitor cells of Trisomy 21. Neurosci. Res. 138:19–25
    [Google Scholar]
  55. 55. 
    Reiche L, Küry P, Göttle P. 2019. Aberrant oligodendrogenesis in Down syndrome: shift in gliogenesis?. Cells 8:1591
    [Google Scholar]
  56. 56. 
    Arbones ML, Thomazeau A, Nakano-Kobayashi A, Hagiwara M, Delabar JM. 2019. DYRK1A and cognition: a lifelong relationship. Pharmacol. Ther. 194:199–221
    [Google Scholar]
  57. 57. 
    Jarhad DB, Mashelkar KK, Kim HR, Noh M, Jeong LS. 2018. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) inhibitors as potential therapeutics. J. Med. Chem. 61:9791–810
    [Google Scholar]
  58. 58. 
    Stagni F, Giacomini A, Emili M, Trazzi S, Guidi S et al. 2016. Short- and long-term effects of neonatal pharmacotherapy with epigallocatechin-3-gallate on hippocampal development in the Ts65Dn mouse model of Down syndrome. Neuroscience 333:277–301
    [Google Scholar]
  59. 59. 
    Hamner T, Udhnani MD, Osipowicz KZ, Lee NR. 2018. Pediatric brain development in Down syndrome: a field in its infancy. J. Int. Neuropsychol. Soc. 24:966–76
    [Google Scholar]
  60. 60. 
    Figueroa-Jimenez MD, Cañete-Massé C, Carbó-Carreté M, Zarabozo-Hurtado D, Peró-Cebollero M et al. 2021. Resting-state default mode network connectivity in young individuals with Down syndrome. Brain Behav 11:e01905
    [Google Scholar]
  61. 61. 
    Vicari S, Bellucci S, Carlesimo GA. 2005. Visual and spatial long-term memory: differential pattern of impairments in Williams and Down syndromes. Dev. Med. Child Neurol. 47:305–11
    [Google Scholar]
  62. 62. 
    Godfrey M, Lee NR 2020. A comprehensive examination of the memory profile of youth with Down syndrome in comparison to typically developing peers. Child Neuropsychol 26:721–38
    [Google Scholar]
  63. 63. 
    Pennington BF, Moon J, Edgin J, Stedron J, Nadel L. 2003. The neuropsychology of Down syndrome: evidence for hippocampal dysfunction. Child Dev 74:75–93
    [Google Scholar]
  64. 64. 
    Byrne A, MacDonald J, Buckley S. 2002. Reading, language and memory skills: a comparative longitudinal study of children with Down syndrome and their mainstream peers. Br. J. Educ. Psychol. 72:513–29
    [Google Scholar]
  65. 65. 
    Jarrold C, Baddeley AD, Phillips C. 2007. Long-term memory for verbal and visual information in Down syndrome and Williams syndrome: performance on the Doors and People test. Cortex 43:233–47
    [Google Scholar]
  66. 66. 
    Vicari S. 2001. Implicit versus explicit memory function in children with Down and Williams syndrome. Down Syndr. Res. Pract. 7:35–40
    [Google Scholar]
  67. 67. 
    Grieco J, Pulsifer M, Seligsohn K, Skotko B, Schwartz A. 2015. Down syndrome: cognitive and behavioral functioning across the lifespan. Am. J. Med. Genet. C Semin. Med. Genet. 169:135–49
    [Google Scholar]
  68. 68. 
    Yang Y, Conners FA, Merrill EC. 2014. Visuo-spatial ability in individuals with Down syndrome: Is it really a strength?. Res. Dev. Disabil. 35:1473–500
    [Google Scholar]
  69. 69. 
    Tungate AS, Conners FA. 2021. Executive function in Down syndrome: a meta-analysis. Res. Dev. Disabil. 108:103802
    [Google Scholar]
  70. 70. 
    Capone G, Goyal P, Ares W, Lannigan E. 2006. Neurobehavioral disorders in children, adolescents, and young adults with Down syndrome. Am. J. Med. Genet. C Semin. Med. Genet. 142C:158–72
    [Google Scholar]
  71. 71. 
    Dykens EM, Shah B, Davis B, Baker C, Fife T, Fitzpatrick J. 2015. Psychiatric disorders in adolescents and young adults with Down syndrome and other intellectual disabilities. J. Neurodev. Disord. 7:9
    [Google Scholar]
  72. 72. 
    García-Cerro S, Martínez P, Vidal V, Corrales A, Flórez J et al. 2014. Overexpression of Dyrk1A is implicated in several cognitive, electrophysiological and neuromorphological alterations found in a mouse model of Down syndrome. PLOS ONE 9:e106572
    [Google Scholar]
  73. 73. 
    Jiang X, Liu C, Yu T, Zhang L, Meng K et al. 2015. Genetic dissection of the Down syndrome critical region. Hum. Mol. Genet. 24:6540–51
    [Google Scholar]
  74. 74. 
    Martínez Cué C, Dierssen M 2020. Plasticity as a therapeutic target for improving cognition and behavior in Down syndrome. Prog. Brain Res. 251:269–302
    [Google Scholar]
  75. 75. 
    De la Torre R, De Sola S, Pons M, Duchon A, de Lagran MM et al. 2014. Epigallocatechin-3-gallate, a DYRK1A inhibitor, rescues cognitive deficits in Down syndrome mouse models and in humans. Mol. Nutr. Food Res. 58:278–88
    [Google Scholar]
  76. 76. 
    Stringer M, Abeysekera I, Thomas J, LaCombe J, Stancombe K et al. 2017. Epigallocatechin-3-gallate (EGCG) consumption in the Ts65Dn model of Down syndrome fails to improve behavioral deficits and is detrimental to skeletal phenotypes. Physiol. Behav. 177:230–41
    [Google Scholar]
  77. 77. 
    De la Torre R, de Sola S, Hernandez G, Farre M, Pujol J et al. 2016. Safety and efficacy of cognitive training plus epigallocatechin-3-gallate in young adults with Down's syndrome (TESDAD): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Neurol 15:801–10
    [Google Scholar]
  78. 78. 
    Latchney SE, Jaramillo TC, Rivera PD, Eisch AJ, Powell CM 2015. Chronic P7C3 treatment restores hippocampal neurogenesis. Neurosci. Lett 591:86–92
    [Google Scholar]
  79. 79. 
    Bianchi P, Ciani E, Contestabile A, Guidi S, Bartesaghi R 2010. Lithium restores neurogenesis in the subventricular zone of the Ts65Dn mouse, a model for Down syndrome. Brain Pathol 20:106–18
    [Google Scholar]
  80. 80. 
    Kleschevnikov AM, Belichenko PV, Villar AJ, Epstein CJ, Malenka RC, Mobley WC. 2004. Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome. J. Neurosci. 24:8153–60
    [Google Scholar]
  81. 81. 
    Kleschevnikov AM, Belichenko PV, Gall J, George L, Nosheny R et al. 2012. Increased efficiency of the GABAA and GABAB receptor-mediated neurotransmission in the Ts65Dn mouse model of Down syndrome. Neurobiol. Dis. 45:683–91
    [Google Scholar]
  82. 82. 
    Fernandez F, Morishita W, Zuniga E, Nguyen J, Blank M et al. 2007. Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome. Nat. Neurosci. 10:411–13
    [Google Scholar]
  83. 83. 
    Rueda N, Flórez J, Martínez-Cué C. 2008. Chronic pentylenetetrazole but not donepezil treatment rescues spatial cognition in Ts65Dn mice, a model for Down syndrome. Neurosci. Lett. 433:22–27
    [Google Scholar]
  84. 84. 
    Braudeau J, Delatour B, Duchon A, Pereira PL, Dauphinot L et al. 2011. Specific targeting of the GABA-A receptor α5 subtype by a selective inverse agonist restores cognitive deficits in Down syndrome mice. J. Psychopharmacol. 25:1030–42
    [Google Scholar]
  85. 85. 
    Deidda G, Parrini M, Naskar S, Bozarth IF, Contestabile A, Cancedda L 2015. Reversing excitatory GABAAR signaling restores synaptic plasticity and memory in a mouse model of Down syndrome. Nat. Med. 21:318–26
    [Google Scholar]
  86. 86. 
    Kleschevnikov AM, Yu J, Kim J, Lysenko LV, Zeng Z et al. 2017. Evidence that increased Kcnj6 gene dose is necessary for deficits in behavior and dentate gyrus synaptic plasticity in the Ts65Dn mouse model of Down syndrome. Neurobiol. Dis. 103:1–10
    [Google Scholar]
  87. 87. 
    Costa ACS, Scott-McKean JJ, Stasko MR. 2008. Acute injections of the NMDA receptor antagonist memantine rescue performance deficits of the Ts65Dn mouse model of Down syndrome on a fear conditioning test. Neuropsychopharmacology 33:1624–32
    [Google Scholar]
  88. 88. 
    Boada R, Hutaff-Lee C, Schrader A, Weitzenkamp D, Benke TA et al. 2012. Antagonism of NMDA receptors as a potential treatment for Down syndrome: a pilot randomized controlled trial. Transl. Psychiatry 2:e141
    [Google Scholar]
  89. 89. 
    Knox D. 2016. The role of basal forebrain cholinergic neurons in fear and extinction memory. Neurobiol. Learn. Mem. 133:39–52
    [Google Scholar]
  90. 90. 
    Heller JH, Spiridigliozzi GA, Crissman BG, Sullivan JA, Eells RL et al. 2006. Safety and efficacy of rivastigmine in adolescents with Down syndrome: a preliminary 20-week, open-label study. J. Child Adolesc. Psychopharmacol. 16:755–65
    [Google Scholar]
  91. 91. 
    Heller JH, Spiridigliozzi GA, Crissman BG, McKillop JA, Yamamoto H, Kishnani PS. 2010. Safety and efficacy of rivastigmine in adolescents with Down syndrome: long-term follow-up. J. Child Adolesc. Psychopharmacol. 20:517–20
    [Google Scholar]
  92. 92. 
    Kishnani PS, Sommer BR, Handen BL, Seltzer B, Capone GT et al. 2009. The efficacy, safety, and tolerability of donepezil for the treatment of young adults with Down syndrome. Am. J. Med. Genet. A 149A:1641–54
    [Google Scholar]
  93. 93. 
    Kishnani PS, Heller JH, Spiridigliozzi GA, Lott I, Escobar L et al. 2010. Donepezil for treatment of cognitive dysfunction in children with Down syndrome aged 10–17. Am. J. Med. Genet. A 152A:3028–35
    [Google Scholar]
  94. 94. 
    Shichiri M, Yoshida Y, Ishida N, Hagihara Y, Iwahashi H et al. 2011. α-Tocopherol suppresses lipid peroxidation and behavioral and cognitive impairments in the Ts65Dn mouse model of Down syndrome. Free Radic. Biol. Med. 50:1801–11
    [Google Scholar]
  95. 95. 
    Lockrow J, Boger H, Bimonte-Nelson H, Granholm AC. Effects of long-term memantine on memory and neuropathology in Ts65Dn mice, a model for Down syndrome. Behav. Brain Res. 221:610–22
    [Google Scholar]
  96. 96. 
    Ellis JM, Tan HK, Gilbert RE, Muller DP, Henley W et al. 2008. Supplementation with antioxidants and folinic acid for children with Down's syndrome: randomised controlled trial. BMJ 336:594–97
    [Google Scholar]
  97. 97. 
    Ashworth M, Palikara O, Van Herwegen J. 2019. Comparing parental stress of children with neurodevelopmental disorders: the case of Williams syndrome, Down syndrome and autism spectrum disorders. J. Appl. Res. Intellect. Disabil. 32:1047–57
    [Google Scholar]
  98. 98. 
    Capone GT, Goyal P, Grados M, Smith B, Kammann H 2008. Risperidone use in children with Down syndrome, severe intellectual disability, and comorbid autistic spectrum disorders: a naturalistic study. J. Dev. Behav. Pediatr. 29:106–16
    [Google Scholar]
  99. 99. 
    Capone GT, Brecher L, Bay M. 2016. Guanfacine use in children with Down syndrome and comorbid attention-deficit hyperactivity disorder (ADHD) with disruptive behaviors. J. Child Neurol. 31:957–64
    [Google Scholar]
  100. 100. 
    del Hoyo Soriano L, Rosser T, Hamilton D, Wood T, Abbeduto L, Sherman S 2020. Gestational age is related to symptoms of attention-deficit/hyperactivity disorder in late-preterm to full-term children and adolescents with Down syndrome. Sci. Rep. 10:20345
    [Google Scholar]
  101. 101. 
    Channell MM, Hahn LJ, Rosser TC, Hamilton D, Frank-Crawford MA et al. 2019. Characteristics associated with autism spectrum disorder risk in individuals with Down syndrome. J. Autism Dev. Disord. 49:3543–56
    [Google Scholar]
  102. 102. 
    Walker JC, Dosen A, Buitelaar JK, Janzing JG. 2011. Depression in Down syndrome: a review of the literature. Res. Dev. Disabil. 32:1432–40
    [Google Scholar]
  103. 103. 
    Marino M, Scala I, Scicolone O, Strisciuglio P, Bravaccio C. 2019. Distribution and age of onset of psychopathological risk in a cohort of children with Down syndrome in developmental age. Ital. J. Pediatr. 45:92
    [Google Scholar]
  104. 104. 
    Cooper SA, Collacott RA. 1994. Clinical features and diagnostic criteria of depression in Down's syndrome. Br. J. Psychiatry 165:399–403
    [Google Scholar]
  105. 105. 
    Myers BA, Pueschel SM. 1995. Major depression in a small group of adults with Down syndrome. Res. Dev. Disabil. 16:285–99
    [Google Scholar]
  106. 106. 
    Palumbo ML, McDougle CJ. 2018. Pharmacotherapy of Down syndrome. Expert Opin. Pharmacother. 19:1875–89
    [Google Scholar]
  107. 107. 
    Santoro SL, Cannon S, Capone G, Franklin C, Hart SJ et al. 2020. Unexplained regression in Down syndrome: 35 cases from an international Down syndrome database. Genet. Med. 22:767–76
    [Google Scholar]
  108. 108. 
    Cardinale KM, Bocharnikov A, Hart SJ, Baker JA, Eckstein C et al. 2019. Immunotherapy in selected patients with Down syndrome disintegrative disorder. Dev. Med. Child Neurol. 61:847–51
    [Google Scholar]
  109. 109. 
    Sullivan KD, Lewis HC, Hill AA, Pandey A, Jackson LP et al. 2016. Trisomy 21 consistently activates the interferon response. eLife 5:e16220
    [Google Scholar]
  110. 110. 
    Mann DM, Yates PO, Marcyniuk B. 1984. Alzheimer's presenile dementia, senile dementia of Alzheimer type and Down's syndrome in middle age form an age related continuum of pathological changes. Neuropathol. Appl. Neurobiol. 10:185–207
    [Google Scholar]
  111. 111. 
    Wisniewski KE, Dalton AJ, McLachlan C, Wen GY, Wisniewski HM 1985. Alzheimer's disease in Down's syndrome: clinicopathologic studies. Neurology 35:957–61
    [Google Scholar]
  112. 112. 
    Coppus A, Evenhuis H, Verberne GJ, Visser F, van Gool P et al. 2006. Dementia and mortality in persons with Down's syndrome. J. Intellect. Disabil. Res. 50:768–77
    [Google Scholar]
  113. 113. 
    McCarron M, McCallion P, Reilly E, Mulryan N 2014. A prospective 14-year longitudinal follow-up of dementia in persons with Down syndrome. J. Intellect. Disabil. Res. 58:61–70
    [Google Scholar]
  114. 114. 
    Sinai A, Mokrysz C, Bernal J, Bohnen I, Bonell S et al. 2018. Predictors of age of diagnosis and survival of Alzheimer's disease in Down syndrome. J. Alzheimer's Dis. 61:717–28
    [Google Scholar]
  115. 115. 
    Prasher VP, Farrer MJ, Kessling AM, Fisher EM, West RJ et al. 1998. Molecular mapping of Alzheimer-type dementia in Down's syndrome. Ann. Neurol. 43:380–83
    [Google Scholar]
  116. 116. 
    Doran E, Keator D, Head E, Phelan MJ, Kim R et al. 2017. Down syndrome, partial trisomy 21, and absence of Alzheimer's disease: the role of APP. J. Alzheimer's Dis. 56:459–70
    [Google Scholar]
  117. 117. 
    Cabrejo L, Guyant-Maréchal L, Laquerrière A, Vercelletto M, De la Fournière F et al. 2006. Phenotype associated with APP duplication in five families. Brain 129:2966–76
    [Google Scholar]
  118. 118. 
    Kasuga K, Shimohata T, Nishimura A, Shiga A, Mizuguchi T et al. 2009. Identification of independent APP locus duplication in Japanese patients with early-onset Alzheimer disease. J. Neurol. Neurosurg. Psychiatry 80:1050–52
    [Google Scholar]
  119. 119. 
    Sleegers K, Brouwers N, Gijselinck I, Theuns J, Goossens D et al. 2006. APP duplication is sufficient to cause early onset Alzheimer's dementia with cerebral amyloid angiopathy. Brain 129:2977–83
    [Google Scholar]
  120. 120. 
    Selkoe DJ, Hardy J. 2016. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol. Med. 8:595–608
    [Google Scholar]
  121. 121. 
    Lemere CA, Blusztajn JK, Yamaguchi H, Wisniewski T, Saido TC, Selkoe DJ. 1996. Sequence of deposition of heterogeneous amyloid β-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol. Dis. 3:16–32
    [Google Scholar]
  122. 122. 
    De Strooper B, Karran E. 2016. The cellular phase of Alzheimer's disease. Cell 164:603–15
    [Google Scholar]
  123. 123. 
    Chen XQ, Mobley WC. 2019. Alzheimer disease pathogenesis: insights from molecular and cellular biology studies of oligomeric Aβ and tau species. Front. Neurosci. 13:659
    [Google Scholar]
  124. 124. 
    Salehi A, Delcroix JD, Belichenko PV, Zhan K, Wu C et al. 2006. Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration. Neuron 51:29–42
    [Google Scholar]
  125. 125. 
    Salehi A, Faizi M, Colas D, Valletta J, Laguna J et al. 2009. Restoration of norepinephrine-modulated contextual memory in a mouse model of Down syndrome. Sci. Transl. Med. 1:7ra17
    [Google Scholar]
  126. 126. 
    Pensalfini A, Kim S, Subbanna S, Bleiwas C, Goulbourne CN et al. 2020. Endosomal dysfunction induced by directly overactivating Rab5 recapitulates prodromal and neurodegenerative features of Alzheimer's disease. Cell Rep 33:108420
    [Google Scholar]
  127. 127. 
    Chen XQ, Sawa M, Mobley WC. 2018. Dysregulation of neurotrophin signaling in the pathogenesis of Alzheimer disease and of Alzheimer disease in Down syndrome. Free Radic. Biol. Med. 114:52–61
    [Google Scholar]
  128. 128. 
    Xu W, Weissmiller AM, White JA II, Fang F, Wang X et al. 2016. Amyloid precursor protein–mediated endocytic pathway disruption induces axonal dysfunction and neurodegeneration. J. Clin. Investig. 126:1815–33
    [Google Scholar]
  129. 129. 
    Kim S, Sato Y, Mohan PS, Peterhoff C, Pensalfini A et al. 2016. Evidence that the rab5 effector APPL1 mediates APP-βCTF-induced dysfunction of endosomes in Down syndrome and Alzheimer's disease. Mol. Psychiatry 21:707–16
    [Google Scholar]
  130. 130. 
    Jiang Y, Mullaney KA, Peterhoff CM, Che S, Schmidt SD et al. 2010. Alzheimer's-related endosome dysfunction in Down syndrome is Aβ-independent but requires APP and is reversed by BACE-1 inhibition. PNAS 107:1630–35
    [Google Scholar]
  131. 131. 
    Israel MA, Yuan SH, Bardy C, Reyna SM, Mu Y et al. 2012. Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells. Nature 482:216–20
    [Google Scholar]
  132. 132. 
    Hung COY, Livesey FJ 2018. Altered γ-secretase processing of APP disrupts lysosome and autophagosome function in monogenic Alzheimer's disease. Cell Rep 25:3647–60.e2
    [Google Scholar]
  133. 133. 
    Kwart D, Gregg A, Scheckel C, Murphy EA, Paquet D et al. 2019. A large panel of isogenic APP and PSEN1 mutant human iPSC neurons reveals shared endosomal abnormalities mediated by APP β-CTFs, not Aβ. Neuron 104:1022
    [Google Scholar]
  134. 134. 
    Sofroniew MV, Howe CL, Mobley WC. 2001. Nerve growth factor signaling, neuroprotection, and neural repair. Annu. Rev. Neurosci. 24:1217–81
    [Google Scholar]
  135. 135. 
    Chen XQ, Salehi A, Pearn ML, Overk C, Nguyen PD et al. 2021. Targeting increased levels of APP in Down syndrome: Posiphen-mediated reductions in APP and its products reverse endosomal phenotypes in the Ts65Dn mouse model. Alzheimer's Dement 17:271–92
    [Google Scholar]
  136. 136. 
    Cummings J, Lee G, Ritter A, Sabbagh M, Zhong K 2020. Alzheimer's disease drug development pipeline: 2020. Alzheimer's Dement 6:e12050
    [Google Scholar]
  137. 137. 
    Coric V, van Dyck CH, Salloway S, Andreasen N, Brody M et al. 2012. Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch. Neurol. 69:1430–40
    [Google Scholar]
  138. 138. 
    Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B et al. 2013. A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N. Engl. J. Med. 369:341–50
    [Google Scholar]
  139. 139. 
    Fleisher AS, Raman R, Siemers ER, Becerra L, Clark CM et al. 2008. Phase 2 safety trial targeting amyloid β production with a γ-secretase inhibitor in Alzheimer disease. Arch. Neurol. 65:1031–38
    [Google Scholar]
  140. 140. 
    Wagner SL, Zhang C, Cheng S, Nguyen P, Zhang X et al. 2014. Soluble γ-secretase modulators selectively inhibit the production of the 42-amino acid amyloid β peptide variant and augment the production of multiple carboxy-truncated amyloid β species. Biochemistry 53:702–13
    [Google Scholar]
  141. 141. 
    Rynearson KD, Ponnusamy M, Prikhodko O, Xie Y, Zhang C et al. 2021. Preclinical validation of a potent γ-secretase modulator for Alzheimer's disease prevention. J. Exp. Med. 218:e20202560
    [Google Scholar]
  142. 142. 
    Sperling RA, Jack CR Jr., Black SE, Frosch MP, Greenberg SM et al. 2011. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer's Association Research Roundtable Workgroup. Alzheimer's Dement 7:367–85
    [Google Scholar]
  143. 143. 
    Avgerinos KI, Ferrucci L, Kapogiannis D. 2021. Effects of monoclonal antibodies against amyloid-β on clinical and biomarker outcomes and adverse event risks: a systematic review and meta-analysis of phase III RCTs in Alzheimer's disease. Ageing Res. Rev. 68:101339
    [Google Scholar]
  144. 144. 
    Rafii MS, Skotko BG, McDonough ME, Pulsifer M, Evans C et al. 2017. A randomized, double-blind, placebo-controlled, phase II study of oral ELND005 (scyllo-inositol) in young adults with Down syndrome without dementia. J. Alzheimer's Dis. 58:401–11
    [Google Scholar]
  145. 145. 
    Mohan M, Carpenter PK, Bennett C. 2009. Donepezil for dementia in people with Down syndrome. Cochrane Database Syst. Rev. 2009 CD007178
    [Google Scholar]
  146. 146. 
    Mohan M, Bennett C, Carpenter PK 2009. Galantamine for dementia in people with Down syndrome. Cochrane Database Syst. Rev. 2009 CD007656
    [Google Scholar]
  147. 147. 
    Mohan M, Bennett C, Carpenter PK 2009. Rivastigmine for dementia in people with Down syndrome. Cochrane Database Syst. Rev. 2009 CD007658
    [Google Scholar]
  148. 148. 
    Hanney M, Prasher V, Williams N, Jones EL, Aarsland D et al. 2012. Memantine for dementia in adults older than 40 years with Down's syndrome (MEADOWS): a randomised, double-blind, placebo-controlled trial. Lancet 379:528–36
    [Google Scholar]
  149. 149. 
    Lott IT, Doran E, Nguyen VQ, Tournay A, Head E, Gillen DL. 2011. Down syndrome and dementia: a randomized, controlled trial of antioxidant supplementation. Am. J. Med. Genet. A 155A:1939–48
    [Google Scholar]
  150. 150. 
    Sano M, Aisen PS, Andrews HF, Tsai WY, Lai F et al. 2016. Vitamin E in aging persons with Down syndrome: a randomized, placebo-controlled clinical trial. Neurology 86:2071–76
    [Google Scholar]
  151. 151. 
    Snyder HM, Bain LJ, Brickman AM, Carrillo MC, Esbensen AJ et al. 2020. Further understanding the connection between Alzheimer's disease and Down syndrome. Alzheimer's Dement 16:1065–77
    [Google Scholar]
  152. 152. 
    Fortea J, Vilaplana E, Carmona-Iragui M, Benejam B, Videla L et al. 2020. Clinical and biomarker changes of Alzheimer's disease in adults with Down syndrome: a cross-sectional study. Lancet 395:1988–97
    [Google Scholar]
  153. 153. 
    Fortea J, Carmona-Iragui M, Benejam B, Fernández S, Videla L et al. 2018. Plasma and CSF biomarkers for the diagnosis of Alzheimer's disease in adults with Down syndrome: a cross-sectional study. Lancet Neurol 17:860–69
    [Google Scholar]
  154. 154. 
    Hendrix JA, Airey DC, Britton A, Burke AD, Capone GT et al. 2021. Cross-sectional exploration of plasma biomarkers of Alzheimer's disease in Down syndrome: early data from the Longitudinal Investigation for Enhancing Down Syndrome Research (LIFE-DSR) study. J. Clin. Med. 10:1907
    [Google Scholar]
  155. 155. 
    Hithersay R, Baksh RA, Startin CM, Wijeratne P, Hamburg S et al. 2020. Optimal age and outcome measures for Alzheimer's disease prevention trials in people with Down syndrome. Alzheimer's Dement 17:595–604
    [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-041521-103641
Loading
/content/journals/10.1146/annurev-pharmtox-041521-103641
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error