The Accumulation of Copper in the Brain of Down Syndrome Promotes Oxidative Stress: Possible Mechanism Underlying Cognitive Impairment

Overview

Journal J Clin Biochem Nutr

Specialty Biochemistry

Date 2022 Jul 29

PMID 35903608

Authors

Keiichi Ishihara

Affiliations

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Abstract

Individuals with Down syndrome (DS), which is caused by triplication of human chromosome 21 (Hsa21), show numerous characteristic symptoms, such as intellectual disability, an impaired cognitive function, and accelerated aging-like phenotypes. Enhanced oxidative stress is assumed to be implicated as a mechanism underlying many of these symptoms of DS. Some genes coded in Hsa21, such as , , and , are suggested as being involved in the exacerbation of oxidative stress. In addition, enhanced oxidative stress has been recently shown to be caused by dyshomeostasis of the redox-active bio-metal copper in the brain of a mouse model of DS. This review aims to summarize the current knowledge on enhanced oxidative stress in DS and suggest a possible molecular mechanism underlying the cognitive impairment of DS mediated by enhanced oxidative stress.

References

Anandatheerthavarada H, Biswas G, Robin M, Avadhani N . Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuronal cells. J Cell Biol. 2003; 161(1):41-54. PMC: 2172865. DOI: 10.1083/jcb.200207030. View

Helguera P, Pelsman A, Pigino G, Wolvetang E, Head E, Busciglio J . ets-2 promotes the activation of a mitochondrial death pathway in Down's syndrome neurons. J Neurosci. 2005; 25(9):2295-303. PMC: 6726094. DOI: 10.1523/JNEUROSCI.5107-04.2005. View

Chiueh C . Iron overload, oxidative stress, and axonal dystrophy in brain disorders. Pediatr Neurol. 2001; 25(2):138-47. DOI: 10.1016/s0887-8994(01)00266-1. View

Wu Y, Song W . Regulation of RCAN1 translation and its role in oxidative stress-induced apoptosis. FASEB J. 2012; 27(1):208-21. DOI: 10.1096/fj.12-213124. View

Kalamakis G, Brune D, Ravichandran S, Bolz J, Fan W, Ziebell F . Quiescence Modulates Stem Cell Maintenance and Regenerative Capacity in the Aging Brain. Cell. 2019; 176(6):1407-1419.e14. DOI: 10.1016/j.cell.2019.01.040. View

Manna C, Officioso A, Trojsi F, Tedeschi G, Leoncini S, Signorini C . Increased non-protein bound iron in Down syndrome: contribution to lipid peroxidation and cognitive decline. Free Radic Res. 2016; 50(12):1422-1431. DOI: 10.1080/10715762.2016.1253833. View

Lockrow J, Prakasam A, Huang P, Bimonte-Nelson H, Sambamurti K, Granholm A . Cholinergic degeneration and memory loss delayed by vitamin E in a Down syndrome mouse model. Exp Neurol. 2009; 216(2):278-89. PMC: 2704550. DOI: 10.1016/j.expneurol.2008.11.021. View

Ozcelik D, Uzun H . Copper intoxication; antioxidant defenses and oxidative damage in rat brain. Biol Trace Elem Res. 2008; 127(1):45-52. DOI: 10.1007/s12011-008-8219-3. View

Sheppard O, Plattner F, Rubin A, Slender A, Linehan J, Brandner S . Altered regulation of tau phosphorylation in a mouse model of down syndrome aging. Neurobiol Aging. 2011; 33(4):828.e31-44. PMC: 3314962. DOI: 10.1016/j.neurobiolaging.2011.06.025. View

10.

Ishihara K, Kawashita E, Shimizu R, Nagasawa K, Yasui H, Sago H . Copper accumulation in the brain causes the elevation of oxidative stress and less anxious behavior in Ts1Cje mice, a model of Down syndrome. Free Radic Biol Med. 2019; 134:248-259. DOI: 10.1016/j.freeradbiomed.2019.01.015. View

11.

Simon A, Schiapparelli L, Salazar-Colocho P, Cuadrado-Tejedor M, Escribano L, Lopez de Maturana R . Overexpression of wild-type human APP in mice causes cognitive deficits and pathological features unrelated to Abeta levels. Neurobiol Dis. 2008; 33(3):369-78. DOI: 10.1016/j.nbd.2008.11.005. View

12.

Shichiri M, Yoshida Y, Ishida N, Hagihara Y, Iwahashi H, Tamai H . α-Tocopherol suppresses lipid peroxidation and behavioral and cognitive impairments in the Ts65Dn mouse model of Down syndrome. Free Radic Biol Med. 2011; 50(12):1801-11. DOI: 10.1016/j.freeradbiomed.2011.03.023. View

13.

Wegiel J, Dowjat K, Kaczmarski W, Kuchna I, Nowicki K, Frackowiak J . The role of overexpressed DYRK1A protein in the early onset of neurofibrillary degeneration in Down syndrome. Acta Neuropathol. 2008; 116(4):391-407. PMC: 2656568. DOI: 10.1007/s00401-008-0419-6. View

14.

Braithwaite S, Stock J, Lombroso P, Nairn A . Protein phosphatases and Alzheimer's disease. Prog Mol Biol Transl Sci. 2012; 106:343-79. PMC: 3739963. DOI: 10.1016/B978-0-12-396456-4.00012-2. View

15.

Kahlem P, Sultan M, Herwig R, Steinfath M, Balzereit D, Eppens B . Transcript level alterations reflect gene dosage effects across multiple tissues in a mouse model of down syndrome. Genome Res. 2004; 14(7):1258-67. PMC: 442140. DOI: 10.1101/gr.1951304. View

16.

Ema M, Ikegami S, Hosoya T, Mimura J, Ohtani H, Nakao K . Mild impairment of learning and memory in mice overexpressing the mSim2 gene located on chromosome 16: an animal model of Down's syndrome. Hum Mol Genet. 1999; 8(8):1409-15. DOI: 10.1093/hmg/8.8.1409. View

17.

Huang X, Moir R, Tanzi R, Bush A, Rogers J . Redox-active metals, oxidative stress, and Alzheimer's disease pathology. Ann N Y Acad Sci. 2004; 1012:153-63. DOI: 10.1196/annals.1306.012. View

18.

Di Domenico F, Tramutola A, Barone E, Lanzillotta C, Defever O, Arena A . Restoration of aberrant mTOR signaling by intranasal rapamycin reduces oxidative damage: Focus on HNE-modified proteins in a mouse model of down syndrome. Redox Biol. 2019; 23:101162. PMC: 6859577. DOI: 10.1016/j.redox.2019.101162. View

19.

Liu F, Liang Z, Wegiel J, Hwang Y, Iqbal K, Grundke-Iqbal I . Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome. FASEB J. 2008; 22(9):3224-33. PMC: 2518253. DOI: 10.1096/fj.07-104539. View

20.

Piccoli C, Izzo A, Scrima R, Bonfiglio F, Manco R, Negri R . Chronic pro-oxidative state and mitochondrial dysfunctions are more pronounced in fibroblasts from Down syndrome foeti with congenital heart defects. Hum Mol Genet. 2012; 22(6):1218-32. DOI: 10.1093/hmg/dds529. View