人血丙种球蛋白通过多种机制在阿尔茨海默病的小鼠模型中提供针对 Aβ 毒性的保护。
Human intravenous immunoglobulin provides protection against Aβ toxicity by multiple mechanisms in a mouse model of Alzheimer's disease.
机构信息
Department of Neurobiology, A, I, Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
出版信息
J Neuroinflammation. 2010 Dec 7;7:90. doi: 10.1186/1742-2094-7-90.
BACKGROUND
Purified intravenous immunoglobulin (IVIG) obtained from the plasma of healthy humans is indicated for the treatment of primary immunodeficiency disorders associated with defects in humoral immunity. IVIG contains naturally occurring auto-antibodies, including antibodies (Abs) against β-amyloid (Aβ) peptides accumulating in the brains of Alzheimer's disease (AD) patients. IVIG has been shown to alleviate AD pathology when studied with mildly affected AD patients. Although its mechanisms-of-action have been broadly studied, it remains unresolved how IVIG affects the removal of natively formed brain Aβ deposits by primary astrocytes and microglia, two major cell types involved in the neuroinflammatory responses.
METHODS
We first determined the effect of IVIG on Aβ toxicity in primary neuronal cell culture. The mechanisms-of-action of IVIG in reduction of Aβ burden was analyzed with ex vivo assay. We studied whether IVIG solubilizes natively formed Aβ deposits from brain sections of APP/PS1 mice or promotes Aβ removal by primary glial cells. We determined the role of lysosomal degradation pathway and Aβ Abs in the IVIG-promoted reduction of Aβ. Finally, we studied the penetration of IVIG into the brain parenchyma and interaction with brain deposits of human Aβ in a mouse model of AD in vivo.
RESULTS
IVIG was protective against Aβ toxicity in a primary mouse hippocampal neuron culture. IVIG modestly inhibited the fibrillization of synthetic Aβ1-42 but did not solubilize natively formed brain Aβ deposits ex vivo. IVIG enhanced microglia-mediated Aβ clearance ex vivo, with a mechanism linked to Aβ Abs and lysosomal degradation. The IVIG-enhanced Aβ clearance appears specific for microglia since IVIG did not affect Aβ clearance by astrocytes. The cellular mechanisms of Aβ clearance we observed have potential relevance in vivo since after peripheral administration IVIG penetrated to mouse brain tissue reaching highest concentrations in the hippocampus and bound selectively to Aβ deposits in co-localization with microglia.
CONCLUSIONS
Our results demonstrate that IVIG promotes recognition and removal of natively formed brain Aβ deposits by primary microglia involving natural Aβ Abs in IVIG. These findings may have therapeutic relevance in vivo as IVIG penetrates through the blood-brain barrier and specifically binds to Aβ deposits in brain parenchyma.
背景
从健康人血浆中提取的纯化静脉注射免疫球蛋白（IVIG）用于治疗与体液免疫缺陷相关的原发性免疫缺陷疾病。IVIG 含有天然存在的自身抗体，包括在阿尔茨海默病（AD）患者大脑中积累的β-淀粉样蛋白（Aβ）肽的抗体（Abs）。在研究轻度 AD 患者时，已经表明 IVIG 可以减轻 AD 病理。尽管已经广泛研究了其作用机制，但仍未解决 IVIG 如何影响原代星形胶质细胞和小胶质细胞这两种参与神经炎症反应的主要细胞类型对天然形成的脑 Aβ 沉积物的清除。
方法
我们首先确定了 IVIG 对原代神经元细胞培养中 Aβ 毒性的影响。使用离体测定法分析 IVIG 减少 Aβ 负担的作用机制。我们研究了 IVIG 是否可从 APP/PS1 小鼠脑切片中溶解天然形成的 Aβ 沉积物或促进原代神经胶质细胞清除 Aβ。我们确定了溶酶体降解途径和 Aβ Abs 在 IVIG 促进的 Aβ 减少中的作用。最后，我们在 AD 小鼠模型中研究了 IVIG 进入脑实质的穿透性及其与脑内人 Aβ 沉积物的相互作用。
结果
IVIG 可在原代小鼠海马神经元培养物中抵抗 Aβ 毒性。IVIG 适度抑制了合成的 Aβ1-42 的纤维化，但离体不能溶解天然形成的脑 Aβ 沉积物。IVIG 增强了小胶质细胞介导的 Aβ 清除作用，其机制与 Aβ Abs 和溶酶体降解有关。IVIG 增强的 Aβ 清除作用似乎对小胶质细胞具有特异性，因为 IVIG 不会影响星形胶质细胞对 Aβ 的清除。我们观察到的 Aβ 清除的细胞机制在体内具有潜在的相关性，因为在周围给药后，IVIG 穿透到小鼠脑组织中，在海马中达到最高浓度，并选择性地与小胶质细胞共定位结合到 Aβ 沉积物上。
结论
我们的研究结果表明，IVIG 通过 IVIG 中的天然 Aβ Abs 促进原代小胶质细胞对天然形成的脑 Aβ 沉积物的识别和清除。这些发现可能具有体内治疗相关性，因为 IVIG 通过血脑屏障穿透，并特异性地结合到脑实质中的 Aβ 沉积物上。
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