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首页> 外文期刊>Amyloid: the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis >Apolipoprotein e increases cell association of amyloid-β 40 through heparan sulfate and LRP1 dependent pathways
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Apolipoprotein e increases cell association of amyloid-β 40 through heparan sulfate and LRP1 dependent pathways

机译:载脂蛋白e通过硫酸乙酰肝素和LRP1依赖性途径增加淀粉样β40的细胞缔合

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摘要

The increased risk of Alzheimer's disease (AD) associated with specific apolipoprotein E (ApoE) isoforms appears to relate to altered amyloid-β (Aβ) homeostasis. Clearance of Aβ from the brain is reduced in the presence of the AD-associated ApoE4 isoform, which may contribute to the accumulation of Aβ deposits in the parenchyma and vasculature. The low-density lipoprotein receptor-related protein 1 (LRP1) and heparan sulfate proteoglycans (HSPGs), both established ApoE receptors, are involved in Aβ uptake, with LRP1 additionally implicated in Aβ transcytosis across the blood-brain barrier. In this study, we detected the co-distribution of heparan sulfate (HS), ApoE and LRP1 in Aβ(1-40)-positive brain microvessels from individuals with Down's syndrome diagnosed with AD. In addition, ApoE was pulled-down from AD cerebrospinal fluid with anti-Aβ antibodies. Using Chinese hamster ovary cells deficient in HS or LRP1, we found that ApoE increases cell association of Aβ in a HSPG- and LRP1-dependent manner; and further, ApoE processing is altered in the absence of cellular HS. These interactions may facilitate Aβ clearance from the brain, but if overwhelmed could contribute to Aβ accumulation and the pathogenesis of AD.
机译:与特定载脂蛋白E(ApoE)亚型相关的阿尔茨海默氏病(AD)风险增加似乎与淀粉样β(Aβ)稳态改变有关。在存在AD相关的ApoE4同工型的情况下,大脑中Aβ的清除减少,这可能有助于实质中和脉管系统中Aβ沉积物的积累。已建立的ApoE受体的低密度脂蛋白受体相关蛋白1(LRP1)和硫酸乙酰肝素蛋白聚糖(HSPG)与Aβ的摄取有关,另外LRP1还涉及跨血脑屏障的Aβ胞吞作用。在这项研究中,我们从诊断为AD的唐氏综合症患者的Aβ(1-40)阳性脑微血管中检测到了硫酸乙酰肝素(HS),ApoE和LRP1的共分布。此外,使用抗Aβ抗体将ApoE从AD脑脊髓液中拉下。使用缺乏HS或LRP1的中国仓鼠卵巢细胞,我们发现ApoE以HSPG和LRP1依赖性方式增加了Aβ的细胞缔合。而且,在没有细胞HS的情况下ApoE的加工过程也发生了改变。这些相互作用可能促进Aβ从大脑清除,但如果不知所措可能会促进Aβ积累和AD的发病机理。

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