巨噬細(xì)胞譜系細(xì)胞來源的遷移體激活腦淀粉樣血管病小鼠模型中補(bǔ)體依賴性血腦屏障損傷

中文摘要：

腦血管中β淀粉樣蛋白（β-β）的積累會損害腦淀粉樣血管病（CAA）中的血腦屏障（BBB）完整性。巨噬細(xì)胞譜系細(xì)胞清除 Aβ 并產(chǎn)生疾病緩解介質(zhì)。在此，我們報(bào)告了Aβ40誘導(dǎo)的巨噬細(xì)胞衍生的遷移體粘在CAA患者的皮膚活檢樣本和CAA小鼠模型（Tg-SwDI/B和5xFAD小鼠）的腦組織上的血管上。我們表明，CD5L 被包裝在遷移體中并對接到血管中，并且 CD5L 的富集會損害對補(bǔ)體激活的抵抗力。血液中巨噬細(xì)胞和膜攻擊復(fù)合物 （MAC） 的遷移體產(chǎn)生能力增加與患者和 Tg-SwDI/B 小鼠的疾病嚴(yán)重程度相關(guān)。值得注意的是，補(bǔ)體抑制治療可防止 Tg-SwDI/B 小鼠遷移體介導(dǎo)的血腦屏障損傷。因此，我們提出巨噬細(xì)胞衍生的遷移體和隨之而來的補(bǔ)體激活是 CAA 中潛在的生物標(biāo)志物和治療靶點(diǎn)。

英文摘要：

Accumulation of amyloid beta protein (Aβ) in brain vessels damages blood brain barrier (BBB) integrity in cerebral amyloid angiopathy (CAA). Macrophage lineage cells scavenge Aβ and produce disease-modifying mediators. Herein, we report that Aβ40-induced macrophage-derived migrasomes are sticky to blood vessels in skin biopsy samples from CAA patients and brain tissue from CAA mouse models (Tg-SwDI/B and 5xFAD mice). We show that CD5L is packed in migrasomes and docked to blood vessels, and that enrichment of CD5L impairs the resistance to complement activation. Increased migrasome-producing capacity of macrophages and membrane attack complex (MAC) in blood are associated with disease severity in both patients and Tg-SwDI/B mice. Of note, complement inhibitory treatment protects against migrasomes-mediated blood-brain barrier injury in Tg-SwDI/B mice. We thus propose that macrophage-derived migrasomes and the consequent complement activation are potential biomarkers and therapeutic targets in CAA.

論文信息：

論文題目：Macrophage lineage cells-derived migrasomes activate complement-dependent blood-brain barrier damage in cerebral amyloid angiopathy mouse model

期刊名稱：Nature Communications

時(shí)間期卷：14, Article number: 3945 (2023)

在線時(shí)間：2023年7月4日

DOI：doi.org/10.1038/s41467-023-39693-x

產(chǎn)品信息：

貨號：CP-005-005

規(guī)格：5ml+5ml

品牌：Liposoma

產(chǎn)地：荷蘭

名稱：Clodronate Liposomes and Control Liposomes

辦事處：Target Technology(靶點(diǎn)科技)

Clodronate Liposomes氯膦酸鹽脂質(zhì)體清除血管周圍巨噬細(xì)胞（Perivascular macrophages，PVMs）和外周血液單核細(xì)胞，疾病模型為：腦淀粉樣血管病（CAA小鼠）。CAA是一種神經(jīng)系統(tǒng)疾病，可導(dǎo)致毀滅性的中風(fēng)和癡呆。AD和CAA這兩種疾病都會導(dǎo)致認(rèn)知能力下降，并且都會導(dǎo)致大腦呈現(xiàn)淀粉樣蛋白沉積。荷蘭Liposoma巨噬細(xì)胞清除劑Clodronate Liposomes見刊于Nature Communications：巨噬細(xì)胞譜系細(xì)胞來源的遷移體激活腦淀粉樣血管病小鼠模型中補(bǔ)體依賴性血腦屏障損傷。

Liposoma巨噬細(xì)胞清除劑Clodronate Liposomes氯膦酸二鈉脂質(zhì)體的材料和方法：

Cell depletion

Peripheral blood monocyte depletion was carried out according to published procedure. Clodronate liposomes (Liposoma, 10?ml/kg, i.p.) was administered to 12-week-old Tg-SwDI/B mice every 3 days to deplete peripheral monocytes/macrophages prior to sacrifice at day 7. Depletion efficacy was confirmed with flow cytometric analysis.

For microglia depletion, PLX5622 was supplied to 12-week-old Tg-SwDI/B mice in the diet at 1200 PPM (1200?mg/kg of chow), starting 7 days prior to sacrifice. Depletion efficacy of was confirmed with immunostaining.

Perivascular macrophage depletion was carried out according to published procedure. 12-week-old Tg-SwDI/B mice were anesthetized with isoflurane and stereotaxically injected with 10?μL of clodronate-containing liposomes into the left lateral ventricle (coordinates from Bregma: anteroposterior, 0.2?mm; mediolateral, 1.2?mm; dorsoventral, 2.3?mm). Animals were sacrificed 7 days later and brains were processed for further analysis. Depletion efficacy of was confirmed with immunostaining.

材料和方法文獻(xiàn)截圖：