Ye-Ran Wang, Xiao-Qin Zeng, Jun Wang, Christopher J. Fowler, Qiao-Xin Li, Xian-Le Bu, James Doecke, Paul Maruff, Ralph N. Martins, Christopher C. Rowe, Colin L. Masters, Yan-Jiang Wang, Yu-Hui Liu
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The AIBL cohort included 162 Aβ-PET<sup>−</sup> CN, 169 Aβ-PET<sup>+</sup> cognitively normal subjects (preclinical AD), and 31 Aβ-PET<sup>+</sup> cognitively impaired subjects (Clinical AD). Plasma autoantibodies to BACE1 were determined by one-site Elisa. The associations of plasma autoantibodies to BACE1 with brain Aβ load and cognitive trajectory were investigated. The effects of autoantibodies to BACE1 on AD-type pathologies and underlying mechanisms were investigated in APP/PS1 mice and SH/APPswe/PS1wt cell lines. In the Chongqing cohort, plasma autoantibodies to BACE1 were higher in AD patients, in comparison with CN and non-AD dementia patients. In the AIBL cohort, plasma autoantibodies to BACE1 were highest in clinical AD patients, followed by preclinical AD and CN subjects. Higher autoantibodies to BACE1 were associated with an increased incidence of brain amyloid positivity conversion during follow-up. 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引用次数: 0
摘要
阿尔茨海默氏症（AD）患者体内的自身抗体谱出现失调。人体血液中存在β位点淀粉样前体蛋白（APP）清除酶1（BACE1）的自身抗体。本研究旨在探讨BACE1自身抗体在AD中的临床意义和病理生理学作用。临床研究在两个独立队列（重庆队列和澳大利亚影像、生物标记和生活方式队列）中进行。重庆队列包括 55 名 AD 患者、28 名非 AD 痴呆症患者和 70 名认知能力正常的受试者（CN）。AIBL队列包括162名Aβ-PET- CN患者、169名Aβ-PET+认知功能正常者（临床前AD）和31名Aβ-PET+认知功能受损者（临床AD）。血浆中的BACE1自身抗体通过单点Elisa法测定。研究了血浆中的BACE1自身抗体与大脑Aβ负荷和认知轨迹之间的关系。在APP/PS1小鼠和SH/APPswe/PS1wt细胞系中研究了BACE1自身抗体对AD型病变的影响及其内在机制。在重庆队列中，AD患者的血浆BACE1自身抗体高于CN和非AD痴呆患者。在AIBL队列中，血浆BACE1自身抗体在临床AD患者中最高，其次是临床前AD和CN受试者。BACE1自身抗体越高，随访期间脑淀粉样蛋白阳性转换的发生率越高。BACE1自身抗体会加剧APP/PS1小鼠的脑淀粉样蛋白沉积和随后的AD型病变，包括Tau高磷酸化、神经炎症和神经退行性变。BACE1自身抗体通过抑制PPARγ信号传导来促进BACE1的表达，从而增加了Aβ的产生。这些发现表明，BACE1自身抗体是AD的致病因子，这些自身抗体的上调可能会促进疾病的发展。这项研究从自身免疫的角度对AD的发病机制提出了新的见解。
Autoantibodies to BACE1 promote Aβ accumulation and neurodegeneration in Alzheimer’s disease
The profile of autoantibodies is dysregulated in patients with Alzheimer’s disease (AD). Autoantibodies to beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) are present in human blood. This study aims to investigate the clinical relevance and pathophysiological roles of autoantibodies to BACE1 in AD. Clinical investigations were conducted in two independent cohorts, the Chongqing cohort, and the Australian Imaging, Biomarkers, and Lifestyle (AIBL) cohort. The Chongqing cohort included 55 AD patients, 28 patients with non-AD dementia, and 70 cognitively normal subjects (CN). The AIBL cohort included 162 Aβ-PET− CN, 169 Aβ-PET+ cognitively normal subjects (preclinical AD), and 31 Aβ-PET+ cognitively impaired subjects (Clinical AD). Plasma autoantibodies to BACE1 were determined by one-site Elisa. The associations of plasma autoantibodies to BACE1 with brain Aβ load and cognitive trajectory were investigated. The effects of autoantibodies to BACE1 on AD-type pathologies and underlying mechanisms were investigated in APP/PS1 mice and SH/APPswe/PS1wt cell lines. In the Chongqing cohort, plasma autoantibodies to BACE1 were higher in AD patients, in comparison with CN and non-AD dementia patients. In the AIBL cohort, plasma autoantibodies to BACE1 were highest in clinical AD patients, followed by preclinical AD and CN subjects. Higher autoantibodies to BACE1 were associated with an increased incidence of brain amyloid positivity conversion during follow-up. Autoantibodies to BACE1 exacerbated brain amyloid deposition and subsequent AD-type pathologies, including Tau hyperphosphorylation, neuroinflammation, and neurodegeneration in APP/PS1 mice. Autoantibodies to BACE1 increased Aβ production by promoting BACE1 expression through inhibiting PPARγ signaling. These findings suggest that autoantibodies to BACE1 are pathogenic in AD and the upregulation of these autoantibodies may promote the development of the disease. This study offers new insights into the mechanism of AD from an autoimmune perspective.
期刊介绍：
Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.
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