预防 APP 转基因小鼠脑脊液中 tau 的增加表明 BACE1 抑制的下游效应。
Prevention of tau increase in cerebrospinal fluid of APP transgenic mice suggests downstream effect of BACE1 inhibition.
机构信息
Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany; Graduate School of Cellular and Molecular Neuroscience, University of Tübingen, Tübingen, Germany.
Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany; Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany.
出版信息
Alzheimers Dement. 2017 Jun;13(6):701-709. doi: 10.1016/j.jalz.2016.09.005. Epub 2016 Oct 14.
INTRODUCTION
The inhibition of the β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is a main therapeutic approach for the treatment of Alzheimer's disease (AD). We previously reported an age-related increase of tau protein in the cerebrospinal fluid (CSF) of amyloid β (Aβ) precursor protein (APP) transgenic mice.
METHODS
APP transgenic mice were treated with a potent BACE1 inhibitor. CSF tau and CSF Aβ levels were assessed. A novel high-sensitivity tau sandwich immunoassay was developed.
RESULTS
We demonstrate that long-term BACE1 inhibition prevents CSF tau increase both in early-depositing APP transgenic mice and APP transgenic mice with moderate Aβ pathology.
DISCUSSION
Our results demonstrate that BACE1 inhibition not only reduces Aβ generation but also downstream AD pathophysiology. The tight correlation between Aβ aggregation in brain and CSF tau levels renders CSF tau a valuable marker to predict the effectiveness of BACE1 inhibitors in current clinical trials.
简介
β-淀粉样前体蛋白裂解酶 1（BACE1）的抑制是治疗阿尔茨海默病（AD）的主要治疗方法。我们之前报道过，在淀粉样 β（Aβ）前体蛋白（APP）转基因小鼠的脑脊液（CSF）中，tau 蛋白随年龄增长而增加。
方法
用一种有效的 BACE1 抑制剂处理 APP 转基因小鼠。评估 CSF 中的 tau 和 Aβ 水平。开发了一种新型高灵敏度 tau 夹心免疫测定法。
结果
我们证明，长期抑制 BACE1 不仅可以预防早期沉积的 APP 转基因小鼠和具有中度 Aβ 病理学的 APP 转基因小鼠的 CSF tau 增加。
讨论
我们的结果表明，BACE1 抑制不仅减少 Aβ 的产生，而且还减少 AD 的下游病理生理学。脑内 Aβ 聚集与 CSF tau 水平之间的紧密相关性使 CSF tau 成为预测 BACE1 抑制剂在当前临床试验中的有效性的有价值的标志物。
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