Anti-malaria drug artesunate prevents development of amyloid-β pathology in mice by upregulating PICALM at the blood-brain barrier.
Anti-malaria drug artesunate prevents development of amyloid-β pathology in mice by upregulating PICALM at the blood-brain barrier.
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DOI：
10.1186/s13024-023-00597-5
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发表时间：
2023-01-27
影响因子：
15.1
通讯作者：
中科院分区：
文献类型：
--
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PICALM是阿尔茨海默病（AD）最重要的易感因素之一。在人类和小鼠中，PICALM在脑内皮中高度表达。在AD脑中PICALM内皮水平降低。PICALM控制Aβ跨血脑屏障（BBB）转胞吞的几个步骤。其从小鼠脑内皮的损失减少了BBB处的Aβ清除，这导致Aβ病理学，但通过内皮PICALM再表达是可逆的。因此，增加BBB中的PICALM有可能减缓Aβ病理学的发展。为了鉴定可以增加PICALM表达的药物，我们在表达由人PICALM启动子驱动的荧光素酶的HEK 293 t细胞中筛选了2007年FDA批准的药物的文库，然后在人Eahy 926内皮细胞系中进行了二次mRNA筛选。在Picalm缺陷（Picalm+/-）小鼠、Picalm+/-; 5XFAD小鼠和内皮特异性Picalm敲除的Picalmlox/lox; Cdh 5-Cre; 5XFAD小鼠中进行了铅命中的体内研究。我们研究了PICALM在BBB的表达、Aβ病理和从脑到血液的清除、脑血流（CBF）反应、BBB完整性和行为。我们的筛选确定抗疟疾药物青蒿琥酯为主要药物。青蒿琥酯使Eahy 926内皮细胞和Picalm+/−小鼠脑毛细血管中PICALM mRNA和蛋白水平升高2-3倍。与溶剂相比，3月龄Picalm+/−; 5XFAD小鼠的青蒿琥酯治疗（32 mg/kg/天，持续2个月）使脑毛细血管PICALM水平增加2倍，并使皮质和海马中的Aβ42和Aβ40水平以及Aβ和硫磺素S-负荷以及血管Aβ负荷降低34- 51%。青蒿琥酯还使循环Aβ42和Aβ40水平增加2倍，证实Aβ从脑到血液的清除加速。与Aβ病理学减少一致，用青蒿琥酯治疗Picalm+/-; 5XFAD小鼠可改善CBF反应、BBB完整性以及新物体定位和识别、挖洞和筑巢的行为。PICALM的内皮特异性敲除消除了青蒿琥酯在5XFAD小鼠中的所有有益作用，表明内皮PICALM是其治疗作用所必需的。青蒿琥酯可增加BBB中PICALM水平和Aβ清除率，从而预防小鼠中Aβ病理学和功能缺陷的发展，并具有转化为人类AD的潜力。在线版本包含补充材料，可通过10.1186/s13024-023-00597-5获得。
PICALM is one of the most significant susceptibility factors for Alzheimer’s disease (AD). In humans and mice, PICALM is highly expressed in brain endothelium. PICALM endothelial levels are reduced in AD brains. PICALM controls several steps in Aβ transcytosis across the blood-brain barrier (BBB). Its loss from brain endothelium in mice diminishes Aβ clearance at the BBB, which worsens Aβ pathology, but is reversible by endothelial PICALM re-expression. Thus, increasing PICALM at the BBB holds potential to slow down development of Aβ pathology. To identify a drug that could increase PICALM expression, we screened a library of 2007 FDA-approved drugs in HEK293t cells expressing luciferase driven by a human PICALM promoter, followed by a secondary mRNA screen in human Eahy926 endothelial cell line. In vivo studies with the lead hit were carried out in Picalm-deficient (Picalm+/−) mice, Picalm+/−; 5XFAD mice and Picalmlox/lox; Cdh5-Cre; 5XFAD mice with endothelial-specific Picalm knockout. We studied PICALM expression at the BBB, Aβ pathology and clearance from brain to blood, cerebral blood flow (CBF) responses, BBB integrity and behavior. Our screen identified anti-malaria drug artesunate as the lead hit. Artesunate elevated PICALM mRNA and protein levels in Eahy926 endothelial cells and in vivo in brain capillaries of Picalm+/− mice by 2–3-fold. Artesunate treatment (32 mg/kg/day for 2 months) of 3-month old Picalm+/−; 5XFAD mice compared to vehicle increased brain capillary PICALM levels by 2-fold, and reduced Aβ42 and Aβ40 levels and Aβ and thioflavin S-load in the cortex and hippocampus, and vascular Aβ load by 34–51%. Artesunate also increased circulating Aβ42 and Aβ40 levels by 2-fold confirming accelerated Aβ clearance from brain to blood. Consistent with reduced Aβ pathology, treatment of Picalm+/−; 5XFAD mice with artesunate improved CBF responses, BBB integrity and behavior on novel object location and recognition, burrowing and nesting. Endothelial-specific knockout of PICALM abolished all beneficial effects of artesunate in 5XFAD mice indicating that endothelial PICALM is required for its therapeutic effects. Artesunate increases PICALM levels and Aβ clearance at the BBB which prevents development of Aβ pathology and functional deficits in mice and holds potential for translation to human AD. The online version contains supplementary material available at 10.1186/s13024-023-00597-5.
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