循环中人载脂蛋白 J 的存在可减少脑淀粉样血管病转基因小鼠模型中脑微出血的发生。

IF 7.9 1区 医学 Q1 CLINICAL NEUROLOGY
Anna Bonaterra-Pastra, Montse Solé, Silvia Lope-Piedrafita, Maria Lucas-Parra, Laura Castellote, Paula Marazuela, Olalla Pancorbo, David Rodríguez-Luna, Mar Hernández-Guillamon
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引用次数: 0

摘要

背景:脑淀粉样血管病(CAA)的特征是淀粉样蛋白-β(Aβ)沉积在脑血管中,导致小叶脑微出血(CMB)和脑内出血(ICH)。载脂蛋白 J(ApoJ)是一种与 Aβ聚集和清除有关的多功能伴侣蛋白。我们的研究调查了慢性重组人载脂蛋白J(rhApoJ)治疗对具有突出CAA的β淀粉样变性转基因小鼠模型血管的影响:20个月大的APP23 C57BL/6小鼠腹腔注射25剂量的rhApoJ(1毫克/千克)(n = 9)或生理盐水(n = 8)13周,野生型(WT)小鼠注射生理盐水(n = 13)。尸体解剖后的大脑接受了T2*加权磁共振成像(MRI)以检测出血病灶。对治疗后的 Aβ 水平和分布、脑纤维蛋白原渗漏、脑平滑肌肌动蛋白(sma)、血浆基质金属蛋白酶和炎症标志物进行了分析。结果:与生理盐水处理的小鼠相比,rhApoJ 处理的 APP23 出现的皮质 CMB(直径 50-300 μm)(p = 0.012)和皮质大出血(> 300 μm)(p = 0.002)的数量更少,与脑β水平无关。核磁共振成像检测到的出血病灶与纤维蛋白原脑外渗相关(p = 0.011)。此外,rhApoJ 处理的小鼠比生理盐水处理的小鼠有更多的 sma 阳性血管(p = 0.038)。在经 rhApoJ 处理的小鼠中,血浆和偶尔出现的脑膜外血管中检测到了人载脂蛋白 J,但在实质组织中却未检测到,这表明其作用机制是通过外周起作用的。与生理盐水处理组相比,给予 rhApoJ 会导致血浆 Groα (p = 0.035)和 MIP-1α (p = 0.035)水平升高,而 MMP-12 (p = 0.046)水平降低。在急性脑叶ICH患者中,MMP-12血浆水平与较大出血量(p = 0.040)和不规则ICH形状(p = 0.036)相关:结论:对老年 APP23 小鼠进行慢性 rhApoJ 治疗可减少 CMB 的发生,从而改善 CAA 相关的神经血管损伤。我们认为,rhApoJ 可通过调节循环中的 MMP-12 防止血脑屏障(BBB)渗漏和 CMB 的出现。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The presence of circulating human apolipoprotein J reduces the occurrence of cerebral microbleeds in a transgenic mouse model with cerebral amyloid angiopathy.

Background: Cerebral amyloid angiopathy (CAA) is characterized by amyloid-β (Aβ) deposition in cerebral vessels, leading to lobar cerebral microbleeds (CMB) and intracerebral hemorrhages (ICH). Apolipoprotein J (ApoJ) is a multifunctional chaperone related to Aβ aggregation and clearance. Our study investigated the vascular impact of chronic recombinant human Apolipoprotein J (rhApoJ) treatment in a transgenic mouse model of β-amyloidosis with prominent CAA.

Methods: Twenty-month-old APP23 C57BL/6 mice received 25 doses of rhApoJ (1 mg/kg) (n = 9) or saline (n = 8) intraperitoneally for 13 weeks, while Wild-type (WT) mice received saline (n = 13). Postmortem brains underwent T2*-weighted magnetic resonance imaging (MRI) to detect hemorrhagic lesions. Aβ levels and distribution, cerebral fibrinogen leakage, brain smooth muscle actin (sma), and plasma matrix metalloproteinases and inflammatory markers were analyzed after treatments. Additionally, plasma samples from 22 patients with lobar ICH were examined to determine the clinical relevance of the preclinical findings.

Results: rhApoJ-treated APP23 presented fewer cortical CMBs (50-300 μm diameter) (p = 0.012) and cortical larger hemorrhages (> 300 μm) (p = 0.002) than saline-treated mice, independently of Aβ brain levels. MRI-detected hemorrhagic lesions correlated with fibrinogen cerebral extravasation (p = 0.011). Additionally, rhApoJ-treated mice presented higher number of sma-positive vessels than saline-treated mice (p = 0.038). In rhApoJ-treated mice, human ApoJ was detected in plasma and in occasional leptomeningeal vessels, but not in the parenchyma, suggesting that its mechanism of action operates through the periphery. The administration of rhApoJ induced an increase in plasma Groα (p = 0.035) and MIP-1α (p = 0.035) levels, while lower MMP-12 (p = 0.046) levels, compared to the saline-treated group. In acute lobar ICH patients, MMP-12 plasma levels correlated with larger hemorrhage volume (p = 0.040) and irregular ICH shape (p = 0.036).

Conclusions: Chronic rhApoJ treatment in aged APP23 mice ameliorated CAA-related neurovascular damage by reducing the occurrence of CMB. We propose that rhApoJ may prevent blood-brain barrier (BBB) leakage and CMB appearance partly through circulating MMP-12 modulation.

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来源期刊
Alzheimer's Research & Therapy
Alzheimer's Research & Therapy 医学-神经病学
CiteScore
13.10
自引率
3.30%
发文量
172
审稿时长
>12 weeks
期刊介绍: Alzheimer's Research & Therapy is an international peer-reviewed journal that focuses on translational research into Alzheimer's disease and other neurodegenerative diseases. It publishes open-access basic research, clinical trials, drug discovery and development studies, and epidemiologic studies. The journal also includes reviews, viewpoints, commentaries, debates, and reports. All articles published in Alzheimer's Research & Therapy are included in several reputable databases such as CAS, Current contents, DOAJ, Embase, Journal Citation Reports/Science Edition, MEDLINE, PubMed, PubMed Central, Science Citation Index Expanded (Web of Science) and Scopus.
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