患有阿尔茨海默病的唐氏综合征患者大脑中铁含量增加，且伴有与铁死亡一致的脂质过氧化。
Down syndrome with Alzheimer's disease brains have increased iron and associated lipid peroxidation consistent with ferroptosis.
作者信息
Thorwald Max A, Godoy-Lugo Jose A, Kerstiens Elizabeth, Garcia Gilberto, Kim Minhoo, Shemtov Sarah J, Silva Justine, Durra Salma, O'Day Peggy A, Mack Wendy J, Hiniker Annie, Vermulst Marc, Benayoun Bérénice A, Higuchi-Sanabria Ryo, Forman Henry Jay, Head Elizabeth, Finch Caleb E
机构信息
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California, USA.
Department of Pathology and Laboratory Medicine, University of California Medical Sciences, Irvine, California, USA.
出版信息
Alzheimers Dement. 2025 Jun;21(6):e70322. doi: 10.1002/alz.70322.
INTRODUCTION
Cerebral microbleeds (MBs) 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 control (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 twofold higher in DSAD than in CTL and AD. Iron storage proteins and lipid peroxidation were increased in the prefrontal cortex. 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.
HIGHLIGHTS
DSAD has increased ferroptotic-related changes compared to sporadic AD. Lipid rafts that process APP have a loss of protective antioxidant enzymes. Partial and mosaic trisomy lowers the amyloid and iron burden.
引言
脑微出血（MBs）与散发性阿尔茨海默病（AD）以及患有AD的唐氏综合征（DSAD）相关。较高的MB铁含量可能会导致铁介导的脂质过氧化。我们假设淀粉样蛋白沉积与MB铁有关，并且淀粉样前体蛋白（APP）三倍体增加了铁负荷和脂质过氧化。
方法
对认知正常的对照（CTL）、AD以及DSAD ApoE3,3携带者的前额叶皮质和小脑进行检测，以分析脂质筏中参与铁代谢、抗氧化反应和淀粉样蛋白加工的蛋白质。
结果
DSAD中的铁含量比CTL和AD中的高两倍。前额叶皮质中的铁储存蛋白和脂质过氧化增加。AD和DSAD中的谷胱甘肽合成蛋白GCLM均减少了50%。负责膜修复的脂质筏GPx4的活性在AD和DSAD中至少降低了30%。
讨论
DSAD比AD表现出更大程度的脂质过氧化，这与更多的MBs和铁负荷一致。
要点
与散发性AD相比，DSAD中与铁死亡相关的变化增加。处理APP的脂质筏中保护性抗氧化酶减少。部分和嵌合三体降低了淀粉样蛋白和铁负荷。
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