Down Syndrome with Alzheimer's Disease Brains Have Increased Iron and Associated Lipid Peroxidation Consistent with Ferroptosis

Overview

Journal bioRxiv

Date 2025 Feb 20

PMID 39975068

Authors

Max A Thorwald

Jose A Godoy-Lugo

Elizabeth Kerstiens

Gilberto Garcia

Minhoo Kim

Sarah J Shemtov

Justine Silva

Salma Durra

Peggy ODay

Peggy A ODay

Wendy J Mack

Annie Hiniker

Marc Vermulst

Berenice Anath Benayoun

Berenice A Benayoun

Ryo Higuchi-Sanabria

Henry Jay Forman

Elizabeth Head

Caleb E Finch

Affiliations

Soon will be listed here.

Abstract

Introduction: Cerebral microbleeds (MB) are associated with sporadic Alzheimer's Disease (AD) and Down Syndrome with AD (DSAD). Higher MB iron may cause iron mediated lipid peroxidation. We hypothesize that amyloid deposition is linked to MB iron and that amyloid precursor protein (APP) triplication increases iron load and lipid peroxidation.

Methods: Prefrontal cortex and cerebellum of cognitively normal (CTL), AD and DSAD ApoE3,3 carriers were examined for proteins that mediated iron metabolism, antioxidant response, and amyloid processing in lipid rafts.

Results: Iron was 2-fold higher in DSAD than CTL and AD. Iron storage proteins and lipid peroxidation were increased in prefrontal cortex, but not in the cerebellum. The glutathione synthesis protein GCLM was decreased by 50% in both AD and DSAD. Activity of lipid raft GPx4, responsible for membrane repair, was decreased by at least 30% in AD and DSAD.

Discussion: DSAD shows greater lipid peroxidation than AD consistent with greater MBs and iron load.

References

Prasher V, Farrer M, Kessling A, Fisher E, West R, Barber P . Molecular mapping of Alzheimer-type dementia in Down's syndrome. Ann Neurol. 1998; 43(3):380-3. DOI: 10.1002/ana.410430316. View

Salehi A, Ashford J, Mufson E . The Link between Alzheimer's Disease and Down Syndrome. A Historical Perspective. Curr Alzheimer Res. 2015; 13(1):2-6. PMC: 6368451. DOI: 10.2174/1567205012999151021102914. View

Hof P, Bouras C, Perl D, Sparks D, Mehta N, Morrison J . Age-related distribution of neuropathologic changes in the cerebral cortex of patients with Down's syndrome. Quantitative regional analysis and comparison with Alzheimer's disease. Arch Neurol. 1995; 52(4):379-91. DOI: 10.1001/archneur.1995.00540280065020. View

Zhao J, OConnor T, Vassar R . The contribution of activated astrocytes to Aβ production: implications for Alzheimer's disease pathogenesis. J Neuroinflammation. 2011; 8:150. PMC: 3216000. DOI: 10.1186/1742-2094-8-150. View

Schoeppe F, Rossi A, Levin J, Reiser M, Stoecklein S, Ertl-Wagner B . Increased cerebral microbleeds and cortical superficial siderosis in pediatric patients with Down syndrome. Eur J Paediatr Neurol. 2018; 23(1):158-164. DOI: 10.1016/j.ejpn.2018.09.004. View

Bersuker K, Hendricks J, Li Z, Magtanong L, Ford B, Tang P . The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature. 2019; 575(7784):688-692. PMC: 6883167. DOI: 10.1038/s41586-019-1705-2. View

Radi R . Protein tyrosine nitration: biochemical mechanisms and structural basis of functional effects. Acc Chem Res. 2012; 46(2):550-9. PMC: 3577981. DOI: 10.1021/ar300234c. View

Thorwald M, Godoy-Lugo J, Garcia G, Silva J, Kim M, Christensen A . Iron-associated lipid peroxidation in Alzheimer's disease is increased in lipid rafts with decreased ferroptosis suppressors, tested by chelation in mice. Alzheimers Dement. 2025; 21(1):e14541. PMC: 11775463. DOI: 10.1002/alz.14541. View

Zsadanyi S, Morcillo-Nieto A, Aranha M, Aragon I, Arriola-Infante J, Vaque-Alcazar L . Associations of Microbleeds and Their Topography With Imaging and CSF Biomarkers of Alzheimer Pathology in Individuals With Down Syndrome. Neurology. 2024; 103(4):e209676. PMC: 11286286. DOI: 10.1212/WNL.0000000000209676. View

10.

Thorwald M, Sta Maria N, Chakhoyan A, ODay P, Jacobs R, Zlokovic B . Iron chelation by oral deferoxamine treatment decreased brain iron and iron signaling proteins. J Alzheimers Dis. 2025; 103(4):1180-1190. DOI: 10.1177/13872877241313031. View

11.

Maure-Blesa L, Rodriguez-Baz I, Carmona-Iragui M, Fortea J . What Can We Learn About Alzheimer's Disease from People with Down Syndrome?. Curr Top Behav Neurosci. 2024; . DOI: 10.1007/7854_2024_546. View

12.

Castro J, Jung T, Grune T, Siems W . 4-Hydroxynonenal (HNE) modified proteins in metabolic diseases. Free Radic Biol Med. 2016; 111:309-315. DOI: 10.1016/j.freeradbiomed.2016.10.497. View

13.

Mandal P, Saharan S, Tripathi M, Murari G . Brain glutathione levels--a novel biomarker for mild cognitive impairment and Alzheimer's disease. Biol Psychiatry. 2015; 78(10):702-10. DOI: 10.1016/j.biopsych.2015.04.005. View

14.

Oconnell M, Ward R, Baum H, Peters T . The role of iron in ferritin- and haemosiderin-mediated lipid peroxidation in liposomes. Biochem J. 1985; 229(1):135-9. PMC: 1145159. DOI: 10.1042/bj2290135. View

15.

Collingwood J, Chong R, Kasama T, Cervera-Gontard L, Dunin-Borkowski R, Perry G . Three-dimensional tomographic imaging and characterization of iron compounds within Alzheimer's plaque core material. J Alzheimers Dis. 2008; 14(2):235-45. DOI: 10.3233/jad-2008-14211. View

16.

Doll S, Porto Freitas F, Shah R, Aldrovandi M, Costa Da Silva M, Ingold I . FSP1 is a glutathione-independent ferroptosis suppressor. Nature. 2019; 575(7784):693-698. DOI: 10.1038/s41586-019-1707-0. View

17.

Pastore A, Tozzi G, Gaeta L, Giannotti A, Bertini E, Federici G . Glutathione metabolism and antioxidant enzymes in children with Down syndrome. J Pediatr. 2003; 142(5):583-5. DOI: 10.1067/mpd.2003.203. View

18.

Saeed M, Boulos J, Mucklich S, Leich E, Chatterjee M, Klauck S . Disruption of Lipid Raft Microdomains, Regulation of CD38, TP53, and MYC Signaling, and Induction of Apoptosis by Lomitapide in Multiple Myeloma Cells. Cancer Genomics Proteomics. 2022; 19(5):540-555. PMC: 9353726. DOI: 10.21873/cgp.20339. View

19.

Tamagno E, Bardini P, Obbili A, Vitali A, Borghi R, Zaccheo D . Oxidative stress increases expression and activity of BACE in NT2 neurons. Neurobiol Dis. 2002; 10(3):279-88. DOI: 10.1006/nbdi.2002.0515. View

20.

Bouter Y, Liekefeld H, Pichlo S, Westhoff A, Fenn L, Bakrania P . Donanemab detects a minor fraction of amyloid-β plaques in post-mortem brain tissue of patients with Alzheimer's disease and Down syndrome. Acta Neuropathol. 2022; 143(5):601-603. PMC: 9038931. DOI: 10.1007/s00401-022-02418-3. View