Brain Iron Overload Drives Ferroptosis in Down Syndrome Alzheimer's Disease

Down syndrome (DS) is caused by trisomy 21, which triples the gene dosage of the amyloid precursor protein (APP) and accelerates Alzheimer's disease (AD) onset by decades. Nearly half of DS individuals develop AD by age 60. This study investigated whether the higher burden of cerebral microbleeds (MBs) in DS with AD (DSAD) produces a greater iron load and triggers ferroptosis—an iron-dependent, oxidative cell death pathway—more severely than in sporadic AD.

Using postmortem prefrontal cortex and cerebellum tissue from ApoE ε3,3 carriers matched for sex (n=8/group: cognitively normal controls, sporadic AD, DSAD), the team analyzed iron metabolism proteins, antioxidant enzyme systems, lipid peroxidation markers, and APP processing components in lipid rafts (LRs). LRs are cholesterol- and sphingomyelin-rich plasma membrane microdomains where APP cleavage occurs and which are highly vulnerable to oxidative damage due to their polyunsaturated fatty acid content.

Key results showed that total iron was approximately twofold higher in DSAD prefrontal cortex compared to both controls and sporadic AD. Iron storage proteins, including ferritin heavy and light chains, were significantly elevated in DSAD. The lipid peroxidation byproduct 4-hydroxynonenal (HNE), a hallmark of ferroptosis, was markedly increased. The glutamate-cysteine ligase modifier subunit (GCLM), rate-limiting for glutathione (GSH) biosynthesis, was reduced by ~50% in both AD and DSAD relative to controls. Critically, GPx4 activity within lipid rafts—the enzyme responsible for neutralizing phospholipid hydroperoxides and preventing membrane ferroptosis—was reduced by at least 30% in both disease groups. Changes were most pronounced in the prefrontal cortex, with the cerebellum relatively spared, consistent with regional AD vulnerability patterns. Importantly, cases with partial or mosaic trisomy 21 had lower amyloid deposition and iron burdens than full trisomy cases, directly linking APP gene dosage to iron-mediated oxidative damage.

The findings support a mechanistic model in which MBs deposit iron in the brain parenchyma; microglia attempting to clear extravasated blood can release Fe²⁺ that drives Fenton chemistry, generating hydroxyl radicals that peroxidize LR lipids, producing toxic HNE adducts and impairing APP secretase processing. Reduced GSH biosynthesis capacity and compromised LR-resident GPx4 activity amplify this damage, collectively fulfilling criteria for ferroptosis.

This work extends prior findings from the same group in sporadic AD to DSAD, suggesting that ferroptosis is a shared but intensified mechanism in DSAD. The partial/mosaic trisomy data provide a compelling natural genetic dose-response experiment. Therapeutic targeting of iron chelation, GSH restoration, or GPx4 activation in lipid rafts may represent viable strategies for DSAD and sporadic AD alike.