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bioRxiv · 10.1101/2025.02.05.636731

Down syndrome with Alzheimers disease brains have increased iron and associated lipid peroxidation consistent with ferroptosis

Thorwald, M. A.·Godoy-Lugo, J. A.·Kerstiens, E.·Garcia, G.·Kim, M.·Shemtov, S. J.·Silva, J.·Durra, S.·O'Day, P.·Mack, W. J.·Hiniker, A.·Vermulst, M.·Benayoun, B. A.·Higuchi-Sanabria, R.·Forman, H. J.·Head, E.·Finch, C. E.
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Abstract

INTRODUCTIONCerebral microbleeds (MB) are associated with sporadic Alzheimers 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. METHODSPrefrontal 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. RESULTSIron 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. DISCUSSIONDSAD shows greater lipid peroxidation than AD consistent with greater MBs and iron load. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=189 HEIGHT=200 SRC="FIGDIR/small/636731v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@fd0d2aorg.highwire.dtl.DTLVardef@16b65d5org.highwire.dtl.DTLVardef@1eab2ddorg.highwire.dtl.DTLVardef@184e6d2_HPS_FORMAT_FIGEXP M_FIG C_FIG Cerebral microbleeds result in increased brain iron and lipid peroxidation in DSAD consistent with ferroptosis as reported for Alzheimers disease. A{beta}; beta-amyloid peptides, APP; amyloid precursor protein, GCLC; glutathione cysteine ligase catalytic subunit, GCLM; glutathione cysteine modifier subunit, GPx4; glutathione peroxidase 4, HNE; 4-hydroxynonenal. RESEARCH IN CONTEXTO_LISystematic Review: DS is associated with increased microbleeds and brain iron that may be mediated by increased APP from Trisomy 21. To assess potential links between amyloid and iron levels, we examined sporadic and DS with AD brains for amyloid processing and antioxidant enzyme defense in lipid rafts. We further compared DSAD with rare variants of DS: partial and mosaic T21. C_LIO_LIInterpretation: DSAD brains showed greater oxidation of lipid rafts where APP is processed than sporadic AD. Corresponding decreases in lipid raft antioxidant enzymes, despite increased total levels of these antioxidant enzymes, present a new mechanism for aberrant amyloid processing during AD. C_LIO_LIFuture Directions: Iron chelation therapies in combination with amyloid monoclonals may benefit DSAD. C_LI

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Thorwald, M. A., Godoy-Lugo, J. A., Kerstiens, E., Garcia, G., Kim, M., Shemtov, S. J., Silva, J., Durra, S., O'Day, P., Mack, W. J., Hiniker, A., Vermulst, M., Benayoun, B. A., Higuchi-Sanabria, R., Forman, H. J., Head, E., Finch, C. E.. 2025-02-06. Down syndrome with Alzheimers disease brains have increased iron and associated lipid peroxidation consistent with ferroptosis. https://doi.org/10.1101/2025.02.05.636731

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