Down syndrome with Alzheimer's disease brains have increased iron and associated lipid peroxidation consistent with...

Area of Science:

• Neuroscience
• Biochemistry
• Genetics

Background:

• Cerebral microbleeds (MBs) are linked to Alzheimer's disease (AD) and Down syndrome with AD (DSAD).
• Elevated iron in MBs can trigger iron-mediated lipid peroxidation.
• Amyloid precursor protein (APP) triplication may exacerbate iron accumulation and lipid peroxidation.

Purpose of the Study:

• To investigate the relationship between amyloid deposition, iron load, and lipid peroxidation in AD and DSAD.
• To examine proteins involved in iron metabolism, antioxidant response, and amyloid processing within lipid rafts.
• To compare ferroptotic changes in DSAD versus sporadic AD.

Main Methods:

• Analysis of prefrontal cortex and cerebellum from control, AD, and DSAD individuals (ApoE3,3 carriers).
• Assessed proteins mediating iron metabolism, antioxidant response, and amyloid processing in lipid rafts.
• Measured iron levels, iron storage proteins, lipid peroxidation markers, and antioxidant enzyme activity (GCLM, GPx4).

Main Results:

• Iron levels were twofold higher in DSAD compared to controls and AD.
• Increased iron storage proteins and lipid peroxidation were observed in the prefrontal cortex of DSAD and AD.
• Glutathione synthesis protein GCLM decreased by 50% in both AD and DSAD, while lipid raft-associated GPx4 activity decreased by at least 30% in AD and DSAD.

Conclusions:

• DSAD exhibits greater lipid peroxidation and iron load than sporadic AD, correlating with increased microbleeds.
• DSAD shows more significant ferroptotic changes than sporadic AD.
• Impaired antioxidant enzyme activity in lipid rafts involved in APP processing contributes to these findings.