Brain iron doubles in Down syndrome patients in Alzheimer’s disease

According to a new USC study, people with Down syndrome have twice the brains of their brains.

The study found that iron-driven oxidative damage flooded brain cells, causing a specific cell death called iron toxicity, which may explain why the symptoms of Alzheimer’s disease appeared in Down syndrome patients 20 years ago.

The study examined brain tissues of Down syndrome and Alzheimer’s disease (DSAD) and compared them with the only healthy controls of Alzheimer’s disease. Scientists have found that extra iron not only accumulates randomly, but is concentrated in key areas where brain cells process amyloid, a characteristic of Alzheimer’s disease.

Iron amyloid linkage

“This is a major clue that helps explain the unique and early changes we see in the brains of people with Down syndrome. The team believes that iron accumulation comes from microscopic cerebrovascular leaks called micropore leakages, which occur more frequently in people with Down syndrome.

Why does Down syndrome make people both prone to iron accumulation and early Alzheimer’s disease? The answer lies in chromosome 21, and people with Down syndrome have three copies instead of two copies. The chromosome carries the gene of amyloid precursor protein (APP), which means that patients with Down syndrome produce 50% of the protein.

By the age of 60, about half of Down syndrome patients showed signs of Alzheimer’s, twenty years ahead of the general population. The new study shows that additional APP production can create a range of problems: more amyloid, more micro proteins, more iron, and ultimately more brain damage.

When the cell defense system fails

This study reveals how iron kills brain cells through the recently discovered form of cell death. Iron triggers chemical reactions that damage cell membranes made from fatty compounds called lipids. Typically, protective enzymes repair this damage, but the DSAD brain shows weak antioxidant defense systems.

The researchers found that tiny and special areas of the cell membrane that process amyloid (special areas of cells that can process amyloid) cause the greatest damage. These cellular hotspots have tripled oxidative damage in the DSAD brain compared to healthy controls, and have significantly less protective enzymes.

Key findings that change our understanding:

• DSAD brain and Alzheimer’s cases have two times higher iron levels
• Lipid peroxidation damage increased by 65% ​​compared to controls
• Key membrane repair enzyme activity decreased by 70% in affected areas
• Rare Down syndrome variants have fewer applications showing lower iron and longer lifespan

GCLM Discovery

In addition to iron accumulation, researchers have also discovered key vulnerabilities in brain antioxidant production systems. Compared with healthy controls, glutathione in DSAD patients (the brain is the most important antioxidant) is an essential enzyme for glutathione (the brain is the most important antioxidant).

This finding, not highlighted in the initial report, suggests that the brain with Down syndrome faces a dual threat: more iron-driven damage plus the ability to produce protective molecules. This finding helps explain why standard Alzheimer’s treatment is less effective in Down syndrome patients.

Clues of rare situations

The team looked at people with rare “mosaic” or “partial” Down syndrome, where only certain cells have additional chromosomes 21. These patients had 35% less brain iron, and their lifespan was longer than those of the 21 patients with complete trisomy, thereby enhancing the connection between APP gene dose and brain injury.

“These cases really support the idea that the number of applications and the amount of iron that comes with them are very much in terms of disease progression,” said Caleb Finch, senior author of the study.

Therapeutic significance

Iron removal therapy was found as a potential therapy. Early mouse studies have shown that ironing drugs that bind to iron and help clear it from the body may reduce Alzheimer’s-related brain changes.

“Removing iron from the brain or drugs that help strengthen the antioxidant system may bring new hope,” Sowald explained. “We now see how important it is not only to treat the amyloid plaques themselves, but also to factors that may accelerate the development of these plaques.”

For 400,000 Americans with Down syndrome, the study offers hope for targeted therapies that can address their unique biological vulnerability rather than applying a certain size of Alzheimer’s treatment.

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