INGE GRUNDKE-IQBAL AWARD FOR ALZHEIMER’S RESEARCH: NEUROTOXIC REACTIVE ASTROCYTES ARE INDUCED BY ACTIVATED MICROGLIA
INGE GRUNDKE-IQBAL AWARD FOR ALZHEIMER’S RESEARCH: NEUROTOXIC REACTIVE ASTROCYTES ARE INDUCED BY ACTIVATED MICROGLIA
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DOI：
10.1016/j.jalz.2019.06.4616
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发表时间：
2019-07
期刊：
影响因子：
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通讯作者：
S. Liddelow;Kevin A. Guttenplan;L. Clarke;F. C. Bennett;Christopher J. Bohlen;Lucas Schirmer;Mariko L. Bennett-M
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文献类型：
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作者：
S. Liddelow;Kevin A. Guttenplan;L. Clarke;F. C. Bennett;Christopher J. Bohlen;Lucas Schirmer;Mariko L. Bennett-M
背景Umibecestat是一种BACE 1抑制剂，在人体治疗剂量下对BACE 2没有预期的抑制作用。正在进行的世代计划正在评估umibecestat在延迟APOE 4携带者阿尔茨海默病（AD）症状发作方面的有效性。在最近的AD试验中，一些BACE抑制剂与治疗3个月后的轻度认知恶化相关。导致认知恶化的机制仍不清楚。成年小鼠中的条件性BACE 1敲除导致海马苔藓纤维锥体下束中的轴突组织缺陷（Ou-Yang等人，2018），表明生理BACE 1活性与大脑结构的维持之间存在联系。因此，我们研究了umibecestat治疗是否与动物海马体的变化或与人类AD CSF生物标志物的早期变化相关。MethodsRats长期用umibecestat 200 mg/kg/天治疗26周。BACE 1敲除小鼠用于方法开发。采用免疫组织化学方法观察海马。在基线和每日给予2、10、35或85 mg/天umibecestat或安慰剂3个月后，从健康老年人（60-80岁）中获得CSF样本（Neumann et al，2018）。Ab 40，Ab 42，总Tau和磷酸化Tau在大多数的主题（n 107）和神经颗粒蛋白在一个子集（n 1/4 59）使用相关的immunoassays.ResultsSignificant缺陷海马形态（w30%减少锥体束长度）中进行了定量在BACE 1基因敲除小鼠相比，野生型小鼠中得到证实。与溶剂给药相比，在接受umibecestat给药的大鼠的肌肉中未观察到差异（± 5%的变化）。在人体中，治疗3个月后观察到剂量依赖性CSF Ab降低高达90%，与预期一致。未观察到CSF总Tau、磷酸化Tau或神经颗粒蛋白相对于基线的有意义的变化。CSF和Neurolamines.ConclusionsUmibecestat的TREM 2数据也将显示相关海马形态学变化的大鼠或CSF AD生物标志物在健康老年人的变化。这些结果以及其他已完成的研究沿着表明，umibecestat具有足够的安全性和耐受性特征，可用于长期临床研究。
BackgroundUmibecestat is a BACE1 inhibitor with no expected inhibition of BACE2 at therapeutic doses in humans. The ongoing Generation Program is assessing umibecestat’s effectiveness in delaying the onset of Alzheimer’s disease (AD) symptoms in APOE4 carriers. In recent AD trials, some BACE inhibitors have been associated with mild cognitive worsening after 3 months of treatment. The mechanisms leading to cognitive worsening remain unknown. Conditional BACE1 knockout in adult mice resulted in axonal organization defects in the hippocampus mossy fiber infrapyramidal bundle (Ou-Yang et al., 2018), suggesting a link between physiological BACE1 activity and maintenance of brain structures. We therefore investigated if umibecestat treatment is associated with changes in the hippocampus in animals or with early changes in AD CSF biomarkers in humans.MethodsRats were treated chronically with umibecestat 200 mg/kg/day for 26 weeks. BACE1 knockout mice were used for method development. Hippocampi were investigated using immunochemistry methods. CSF samples were obtained from healthy elderly (60-80 years) at baseline and following 3-month daily administration of umibecestat 2, 10, 35 or 85 mg/day or placebo (Neumann et al, 2018). Ab40, Ab42, total Tau, and phosphorylated Tau were quantified in the majority of the subjects (n 107) and neurogranin in a subset (n ¼59) using relevant immunoassays.ResultsSignificant defects in hippocampal morphology (w30% reduction in infrapyramidal bundle length) were confirmed in BACE1 knockout mice compared to wild-type mice. No differences (variations of+/-5%) were observed in hippocampi of rats dosed with umibecestat compared to vehicle-treated. In humans, dose-dependent CSF Ab lowering up to 90% was observed upon 3-months treatment as expected. No meaningful changes from baseline in CSF total Tau, phosphorylated Tau or neurogranin were observed. Data on TREM2 in CSF and Neurofilaments will also be shown.ConclusionsUmibecestat was not associated with relevant hippocampal morphological changes in rats or changes in CSF AD biomarkers in healthy elderly. These results, along with other completed studies, indicate that umibecestat has an adequate safety and tolerability profile for long-term clinical studies.