BACKGROUND Alzheimer's disease (AD) is the most common form of dementia, the number of affected individuals is rising, with significant impacts for healthcare systems. Current symptomatic treatments delay, but do not halt, disease progression. Genetic evidence points to aggregation and deposition of amyloid-β (Aβ) in the brain being causal for the neurodegeneration and dementia typical of AD. Approaches to target Aβ via inhibition of γ-secretase or passive antibody therapy have not yet resulted in substantial clinical benefits. Inhibition of BACE1 (β-secretase) has proven a challenging concept, but recent BACE1inhibitors can enter the brain sufficiently well to lower Aβ. However, failures with the first clinical BACE1 inhibitors have highlighted the need to generate compounds with appropriate efficacy and safety profiles, since long treatment periods are expected to be necessary in humans. RESULTS Treatment with NB-360, a potent and brain penetrable BACE-1 inhibitor can completely block the progression of Aβ deposition in the brains of APP transgenic mice, a model for amyloid pathology. We furthermore show that almost complete reduction of Aβ was achieved also in rats and in dogs, suggesting that these findings are translational across species and can be extrapolated to humans. Amyloid pathology may be an initial step in a complex pathological cascade; therefore we investigated the effect of BACE-1 inhibition on neuroinflammation, a prominent downstream feature of the disease. NB-360 stopped accumulation of activated inflammatory cells in the brains of APP transgenic mice. Upon chronic treatment of APP transgenic mice, patches of grey hairs appeared. CONCLUSIONS In a rapidly developing field, the data on NB-360 broaden the chemical space and expand knowledge on the properties that are needed to make a BACE-1 inhibitor potent and safe enough for long-term use in patients. Due to its excellent brain penetration, reasonable oral doses of NB-360 were sufficient to completely block amyloid-β deposition in an APP transgenic mouse model. Data across species suggest similar treatment effects can possibly be achieved in humans. The reduced neuroinflammation upon amyloid reduction by NB-360 treatment supports the notion that targeting amyloid-β pathology can have beneficial downstream effects on the progression of Alzheimer's disease.

中文翻译：

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新型的BACE抑制剂NB-360在APP转基因小鼠中显示出优异的药理作用，并且淀粉样β和神经炎症明显减少。

背景技术阿尔茨海默氏病（AD）是痴呆的最常见形式，受影响个体的数量正在增加，这对医疗保健系统产生了重大影响。当前的对症治疗延迟但不阻止疾病进展。遗传证据表明，脑内淀粉样β（Aβ）的聚集和沉积是AD典型神经变性和痴呆的原因。通过抑制γ-分泌酶或被动抗体疗法靶向Aβ的方法尚未产生实质性的临床益处。抑制BACE1（β-分泌酶）已被证明是一个具有挑战性的概念，但是最近的BACE1抑制剂可以很好地进入大脑以降低Aβ。然而，首批临床BACE1抑制剂的失败凸显了对产生具有适当功效和安全性的化合物的需求，因为预期人类需要较长的治疗时间。结果NB-360是一种强效且可穿透大脑的BACE-1抑制剂，可完全阻断APP转基因小鼠（一种淀粉样蛋白病理模型）的大脑中Aβ沉积的进程。我们进一步表明，在大鼠和狗中，Aβ也几乎完全减少，这表明这些发现是跨物种翻译的，可以推断给人类。淀粉样蛋白病理可能是复杂病理级联反应的第一步。因此，我们研究了BACE-1抑制对神经炎症（该疾病的主要下游特征）的影响。NB-360阻止了活化的炎症细胞在APP转基因小鼠大脑中的积累。在对APP转基因小鼠进行长期治疗后，出现了白发斑块。结论在快速发展的领域中，NB-360的数据拓宽了化学领域，并扩大了对使BACE-1抑制剂有效且足以长期用于患者的安全性所需的特性的知识。由于其出色的大脑渗透能力，合理的NB-360口服剂量足以完全阻断APP转基因小鼠模型中的β-淀粉样蛋白沉积。跨物种的数据表明，在人类中可能实现相似的治疗效果。通过NB-360治疗减少淀粉样蛋白后神经炎症的减轻支持了以下观点：靶向淀粉样β病理学可以对阿尔茨海默氏病的进展产生有益的下游影响。NB-360上的数据拓宽了化学领域，并扩大了对使BACE-1抑制剂有效且足以长期用于患者的安全性所需的特性的知识。由于其出色的大脑渗透能力，合理的NB-360口服剂量足以完全阻断APP转基因小鼠模型中的β-淀粉样蛋白沉积。跨物种的数据表明，在人类中可能实现相似的治疗效果。通过NB-360治疗减少淀粉样蛋白后神经炎症的减轻支持了以下观点：靶向淀粉样β病理学可以对阿尔茨海默氏病的进展产生有益的下游影响。NB-360上的数据拓宽了化学领域，并扩大了对使BACE-1抑制剂有效且足以长期用于患者的安全性所需的特性的知识。由于其出色的大脑渗透能力，合理的NB-360口服剂量足以完全阻断APP转基因小鼠模型中的β-淀粉样蛋白沉积。跨物种的数据表明，在人类中可能实现相似的治疗效果。通过NB-360治疗减少淀粉样蛋白后神经炎症的减轻支持了以下观点：靶向淀粉样β病理学可以对阿尔茨海默氏病的进展产生有益的下游影响。跨物种的数据表明，在人类中可能实现相似的治疗效果。通过NB-360治疗减少淀粉样蛋白后神经炎症的减少支持了以下观点：靶向淀粉样β蛋白病理学可以对阿尔茨海默氏病的进展产生有益的下游影响。跨物种的数据表明，在人类中可能实现相似的治疗效果。通过NB-360治疗减少淀粉样蛋白后神经炎症的减少支持了以下观点：靶向淀粉样β蛋白病理学可以对阿尔茨海默氏病的进展产生有益的下游影响。