Naturally-Occurring Antibodies Against Bim are Decreased in Alzheimer’s Disease and Attenuate AD-type Pathology in a Mouse Model
Naturally-Occurring Antibodies Against Bim are Decreased in Alzheimer’s Disease and Attenuate AD-type Pathology in a Mouse Model
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DOI：
10.1007/s12264-022-00869-y
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发表时间：
2022-05
影响因子：
5.6
通讯作者：
Jie-Ming Jian;Dong-Yu Fan;Dingyuan Tian;Yuan Cheng;Pu-Yang Sun;Chengcheng Tan;G. Zeng;C. He
中科院分区：
文献类型：
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作者：
Jie-Ming Jian;Dong-Yu Fan;Dingyuan Tian;Yuan Cheng;Pu-Yang Sun;Chengcheng Tan;G. Zeng;C. He
神经细胞凋亡增加是阿尔茨海默病（AD）的重要病理特征。Bcl-2相互作用的细胞死亡介质（Bim）介导淀粉样蛋白β（Aβ）诱导的神经元凋亡。天然存在的抗Bim抗体（NAbs-Bim）存在于人类血液中，其水平和功能在AD中未知。在这项研究中，我们发现AD患者循环中的NAbs-Bim减少。NAbs-Bim的血浆水平与脑淀粉样蛋白负荷呈负相关，与认知功能呈正相关。此外，从静脉注射免疫球蛋白中纯化的NAbs-Bim可改善APP/PS 1小鼠的行为缺陷，减轻Aβ沉积、tau蛋白过度磷酸化、小胶质细胞增生和神经元凋亡，体外研究表明NAbs-Bim可通过中和Bim介导的神经元凋亡和淀粉样前体蛋白的淀粉样加工而对AD起到神经保护作用。这些发现表明NAbs-Bim的减少可能有助于AD的发病机制，并且针对Bim的免疫疗法有望治疗AD。
Increased neuronal apoptosis is an important pathological feature of Alzheimer’s disease (AD). The Bcl-2-interacting mediator of cell death (Bim) mediates amyloid-beta (Aβ)-induced neuronal apoptosis. Naturally-occurring antibodies against Bim (NAbs-Bim) exist in human blood, with their levels and functions unknown in AD. In this study, we found that circulating NAbs-Bim were decreased in AD patients. Plasma levels of NAbs-Bim were negatively associated with brain amyloid burden and positively associated with cognitive functions. Furthermore, NAbs-Bim purified from intravenous immunoglobulin rescued the behavioral deficits and ameliorated Aβ deposition, tau hyperphosphorylation, microgliosis, and neuronal apoptosis in APP/PS1 mice.In vitroinvestigations demonstrated that NAbs-Bim were neuroprotective against AD through neutralizing Bim-directed neuronal apoptosis and the amyloidogenic processing of amyloid precursor protein. These findings indicate that the decrease of NAbs-Bim might contribute to the pathogenesis of AD and immunotherapies targeting Bim hold promise for the treatment of AD.