Widespread severe cerebral elevations of haptoglobin and haemopexin in sporadic Alzheimer's disease: Evidence for a pervasive microvasculopathy.
Widespread severe cerebral elevations of haptoglobin and haemopexin in sporadic Alzheimer's disease: Evidence for a pervasive microvasculopathy.
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散发性阿尔茨海默氏病中触珠蛋白和血红蛋白的广泛严重脑升高：普遍性微血管病变的证据。
DOI：
10.1016/j.bbrc.2021.02.107
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发表时间：
2021
影响因子：
3.1
通讯作者：
Philbert SA
中科院分区：
文献类型：
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作者：
Philbert SA
散发性阿尔茨海默氏病 (sAD) 是与年龄相关的神经退行性变的最常见原因，但目前尚无有效的治疗方法已证明可以缓解疾病。因此，研究迄今为止未知的大脑结构和功能方面，以寻求新的疾病相关机制，这些机制可能是新的疾病缓解干预措施的目标。在 SAD 病例对照研究中进行假设生成蛋白质组学研究期间，我们观察到所研究的所有六个大脑区域中触珠蛋白和血红素结合蛋白普遍升高，这些区域共同代表了大脑的大部分区域。测量到的扰动是显着的，上调的后验概率通常>95%，并且触珠蛋白在大脑深部结构（海马、内嗅皮层和扣带回）以及感觉和运动皮层以及小脑的平均表达水平加倍。触珠蛋白和血红素通常被认为是循环蛋白，其主要功能是分别结合溶血后形成的强促炎细胞外血红蛋白和血红素分子，从而促进它们的清除并抑制它们可能引起的损害，例如急性肾损伤。据我们所知，之前脑触珠蛋白和血红素结合蛋白的升高均未与 sAD 的发病机制相关。这些病例的尸检未显示肉眼可见的脑出血迹象。这些发现表明，触珠蛋白和血红素结合蛋白在大脑中普遍升高，这与低水平的血红蛋白脑内渗漏以及随后整个 sAD 大脑中血红素的形成一致。他们指出，一种广泛存在的潜在微血管病变会促进红细胞渗漏，从而引发游离组织血红蛋白升高，并导致触珠蛋白和血红素结合蛋白的测量升高。
Sporadic Alzheimer’s disease (sAD) is the commonest cause of age-related neurodegeneration but there are no available treatments with demonstrated disease-modifying actions. It is therefore relevant to study hitherto-unknown aspects of brain structure and function to seek new disease-related mechanisms that might be targeted by novel disease-modifying interventions. During hypothesis-generating proteomic investigations in a case-control study of sAD, we observed widespread elevations of haptoglobin and haemopexin in all six brain-regions studied, which together represent much of the brain. Measured perturbations were significant, with the posterior probability of upregulation generally >95% and haptoglobin doubling in expression levels on average across deep brain structures (hippocampus, entorhinal cortex and cingulate gyrus) as well as sensory and motor cortices, and cerebellum. Haptoglobin and haemopexin are often regarded as circulating proteins whose main functions are to bind, respectively, the strongly pro-inflammatory extracellular haemoglobin and haeme molecules that form following haemolysis, thereby promoting their clearance and suppressing damage they might otherwise cause, for example, acute kidney injury. To our knowledge, elevations in neither cerebral haptoglobin nor haemopexin have previously been linked to the pathogenesis of sAD.Post-mortemexamination of these cases showed no signs of macroscopic cerebral haemorrhage. These findings demonstrate pervasive cerebral elevation of haptoglobin and haemopexin, consistent with low-level intracerebral leakage of haemoglobin and consequent haeme formation throughout sAD brain. They point to a widespread underlying microvasculopathy that facilitates erythrocyte leakage, thereby triggering elevated tissue-free haemoglobin and driving the measured elevations in haptoglobin and haemopexin.
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DOI：
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发表时间：
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期刊：
影响因子：
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作者：
Acta Neuropathologica;V. IrinaAlafuzo;D. R. Thal;Thomas Arzberger;Nenad Bogdanovic;S. Al;Istvan Bodi;Susan Boluda;O. Bugiani;Charles Duyckaerts;Ellen Gelpi;S. Gentleman;G. Giaccone;Manuel Graeber;T. Hortobágyi;R. Höftberger;Paul G. Ince;James W. Ironside;Nikolaos Kavantzas;Andrew King;Penelope Korkolopoulou;Gábor G. Kovács;D. Meyronet;C. Monoranu;Tatjana Nilsson;P. Parchi;E. Patsouris;M. Pikkarainen;T. Révész;A. Rozemuller;Danielle Seilhean;Walter Schulz;Nathalie Streichenberger;Stephen B. Wharton;Hans A. Kretzschmar;T. R. Queen;Square Brain Bank;G. G. Fondazione;Istituto;C. Besta;Italy T Milan;Arzberger
通讯作者：
Arzberger
DOI：
10.1136/bjo.47.9.521
发表时间：
1963-09-01
期刊：
The British journal of ophthalmology
影响因子：
--
作者：
ASHTON, N
通讯作者：
ASHTON, N
影响因子：
15.9
作者：
Talbot, Konrad;Wang, Hoau-Yan;Arnold, Steven E.
通讯作者：
Arnold, Steven E.
影响因子：
29
作者：
Akoudad S;Wolters FJ;Viswanathan A;de Bruijn RF;van der Lugt A;Hofman A;Koudstaal PJ;Ikram MA;Vernooij MW
通讯作者：
Vernooij MW