Bordeaux University, Institut des Maladies Neurodégénératives, UMR, 5293, Bordeaux, France.
CNRS, Institut des Maladies Neurodégénératives, UMR, 5293, Bordeaux, France.
Sci Rep. 2019 Mar 8;9(1):3989. doi: 10.1038/s41598-019-40438-4.
Identification of endogenous pathological amyloid β peptides (Aβ) forms in the brains of patients with Alzheimer's disease (AD) is still unclear. In healthy brain, Aβ can associate with Apolipoprotein E (ApoE) which is involved in its metabolism and clearance. In the brain of patients with AD, ApoE is cleaved and produces ApoE fragments. We studied the forms of Aβ and their interaction with the ApoE fragments in post-mortem brains from control and AD patients by western blots and co-immunoprecipitation. Three Aβ-containing peptides and three ApoE fragments were specifically found in the brain of AD patients. Co-immunoprecipitations showed that ApoE fragments and Aβ1-42 peptides are co-partners in heteromers of 18 and 16 kDa while ApoE-fragments and Aβ peptides of 12 kDa did not interact with each other. Formation of the 18 kDa ApoE-fragment/Aβ heteromers is specifically increased in ApoE4 carriers and is a strong brain marker of AD while 16 kDa ApoE-fragment/Aβ and Aβ 12 kDa correlate to memory deficit. These data show that in patients with AD, ApoE fragmentation generates peptides that trap Aβ in the brain. Inhibiting the fragmentation or targeting ApoE fragments could be exploited to define strategies to detect or reverse AD.
在阿尔茨海默病（AD）患者的大脑中，内源性病理性淀粉样β肽（Aβ）的存在形式仍不清楚。在健康的大脑中，Aβ可以与载脂蛋白 E（ApoE）结合，后者参与其代谢和清除。在 AD 患者的大脑中，ApoE 被切割并产生 ApoE 片段。我们通过 Western blot 和免疫共沉淀研究了来自对照和 AD 患者死后大脑中 Aβ的形式及其与 ApoE 片段的相互作用。在 AD 患者的大脑中，我们专门发现了三种含有 Aβ的肽和三种 ApoE 片段。免疫共沉淀表明，ApoE 片段和 Aβ1-42 肽是 18 和 16 kDa 异源三聚体的共同伴侣，而 12 kDa 的 ApoE 片段和 Aβ肽彼此不相互作用。在 ApoE4 携带者中，18 kDa ApoE 片段/Aβ异源三聚体的形成特异性增加，是 AD 的强烈脑标志物，而 16 kDa ApoE 片段/Aβ和 Aβ 12 kDa 与记忆缺陷相关。这些数据表明，在 AD 患者中，ApoE 片段生成的肽将 Aβ困在大脑中。抑制片段化或靶向 ApoE 片段可能被用来定义检测或逆转 AD 的策略。
