Early Aβ reduction prevents progression of cerebral amyloid angiopathy
Early Aβ reduction prevents progression of cerebral amyloid angiopathy
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DOI：
10.1002/ana.25562
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发表时间：
2019-08-19
影响因子：
11.2
通讯作者：
Jucker, Mathias
中科院分区：
文献类型：
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作者：
Schelle, Juliane;Wegenast-Braun, Bettina M.;Jucker, Mathias
目的以β-淀粉样肽（A β）为靶点治疗阿尔茨海默病（AD）的临床试验失败的原因包括选择了错误的AD病理生理学阶段或A β是错误的靶点。靶向A β预防脑淀粉样血管病（CAA）尚未得到严格遵循，尽管A β对CAA和相关血管病的因果作用是无可争议的。CAA发生于正常衰老和不同程度的AD中，其中其影响和治疗被实质A β沉积的存在所混淆。方法APPDutch小鼠在脑实质淀粉样蛋白缺失的情况下发生CAA，模拟遗传性脑出血伴淀粉样变性Dutch型（HCHWA-D）。用β位点淀粉样前体蛋白裂解酶1（BACE 1）抑制剂处理小鼠。我们使用三维超显微镜和免疫测定可视化CAA和评估A β在脑脊液（CSF）和大脑。结果CAA发病时间为22 ~ 24月龄，首先发生于额叶软脑膜和皮质浅血管，其次为穿透皮质层的血管。CSF A β随着年龄的增长而增加，随后在CAA发作时A β 40和A β 42都减少，这支持CSF A β 40和A β 42的联合减少是血管淀粉样蛋白的特异性生物标志物的观点。从CAA发作开始并持续4个月的BACE 1抑制剂治疗显示CSF中A β减少90%，并在很大程度上预防了CAA进展和相关病理。这是第一个研究表明，在疾病早期时间点A β减少在很大程度上防止CAA在缺乏实质淀粉样蛋白。我们的观察为CAA风险患者和症状前HCHWA-D患者的A β降低治疗提供了临床前基础。2019年安神经
Objective Clinical trials targeting beta-amyloid peptides (A beta) for Alzheimer disease (AD) failed for arguable reasons that include selecting the wrong stages of AD pathophysiology or A beta being the wrong target. Targeting A beta to prevent cerebral amyloid angiopathy (CAA) has not been rigorously followed, although the causal role of A beta for CAA and related hemorrhages is undisputed. CAA occurs with normal aging and to various degrees in AD, where its impact and treatment is confounded by the presence of parenchymal A beta deposition. Methods APPDutch mice develop CAA in the absence of parenchymal amyloid, mimicking hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D). Mice were treated with a beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor. We used 3-dimensional ultramicroscopy and immunoassays for visualizing CAA and assessing A beta in cerebrospinal fluid (CSF) and brain. Results CAA onset in mice was at 22 to 24 months, first in frontal leptomeningeal and superficial cortical vessels followed by vessels penetrating the cortical layers. CSF A beta increased with aging followed by a decrease of both A beta 40 and A beta 42 upon CAA onset, supporting the idea that combined reduction of CSF A beta 40 and A beta 42 is a specific biomarker for vascular amyloid. BACE1 inhibitor treatment starting at CAA onset and continuing for 4 months revealed a 90% A beta reduction in CSF and largely prevented CAA progression and associated pathologies. Interpretation This is the first study showing that A beta reduction at early disease time points largely prevents CAA in the absence of parenchymal amyloid. Our observation provides a preclinical basis for A beta-reducing treatments in patients at risk of CAA and in presymptomatic HCHWA-D. ANN NEUROL 2019