German Center for Neurodegenerative Diseases, Tübingen, Germany.
Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Ann Neurol. 2019 Oct;86(4):561-571. doi: 10.1002/ana.25562. Epub 2019 Aug 19.
Clinical trials targeting β-amyloid peptides (Aβ) for Alzheimer disease (AD) failed for arguable reasons that include selecting the wrong stages of AD pathophysiology or Aβ being the wrong target. Targeting Aβ to prevent cerebral amyloid angiopathy (CAA) has not been rigorously followed, although the causal role of Aβ 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 Aβ deposition.
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 β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor. We used 3-dimensional ultramicroscopy and immunoassays for visualizing CAA and assessing Aβ in cerebrospinal fluid (CSF) and brain.
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 Aβ increased with aging followed by a decrease of both Aβ40 and Aβ42 upon CAA onset, supporting the idea that combined reduction of CSF Aβ40 and Aβ42 is a specific biomarker for vascular amyloid. BACE1 inhibitor treatment starting at CAA onset and continuing for 4 months revealed a 90% Aβ reduction in CSF and largely prevented CAA progression and associated pathologies.
This is the first study showing that Aβ reduction at early disease time points largely prevents CAA in the absence of parenchymal amyloid. Our observation provides a preclinical basis for Aβ-reducing treatments in patients at risk of CAA and in presymptomatic HCHWA-D. ANN NEUROL 2019;86:561-571.
针对阿尔茨海默病（AD）的β-淀粉样肽（Aβ）的临床试验失败了，其原因有争议，包括选择 AD 病理生理学的错误阶段或 Aβ 是错误的靶点。虽然 Aβ 对 CAA 和相关出血的因果作用无可争议，但靶向 Aβ 预防脑淀粉样血管病（CAA）尚未得到严格遵循。CAA 发生于正常衰老过程中，在 AD 中程度不同，其在脑实质 Aβ 沉积存在的情况下，其影响和治疗效果受到干扰。
APPDutch 小鼠在没有脑实质淀粉样蛋白的情况下发生 CAA，模拟遗传性脑淀粉样血管病伴荷兰型（HCHWA-D）。用β-位淀粉样前体蛋白裂解酶 1（BACE1）抑制剂对小鼠进行治疗。我们使用 3 维超微镜和免疫测定法来可视化 CAA，并评估脑脊液（CSF）和大脑中的 Aβ。
CAA 在小鼠中的发病时间为 22 至 24 个月，首先在前额软脑膜和浅层皮质血管中发生，然后在穿透皮质层的血管中发生。CSF Aβ随年龄增长而增加，随后在 CAA 发病时 Aβ40 和 Aβ42 减少，支持 CSF Aβ40 和 Aβ42 联合减少是血管淀粉样的特异性生物标志物的观点。在 CAA 发病时开始并持续 4 个月的 BACE1 抑制剂治疗显示 CSF 中 Aβ 减少 90%，并在很大程度上阻止了 CAA 的进展和相关病变。
这是第一项研究表明，在没有脑实质淀粉样蛋白的情况下，在疾病早期阶段减少 Aβ 可在很大程度上预防 CAA。我们的观察结果为有发生 CAA 风险的患者和无症状的 HCHWA-D 患者提供了 Aβ 减少治疗的临床前依据。神经病学年鉴 2019；86：561-571。
