靶向澱粉樣蛋白前體可減少後期阿爾茨海默氏樣病理
作者：
小柯機器人發布時間：2020/11/18 13:42:08
德國圖賓根大學Mathias Jucker研究小組發現，在轉基因小鼠中靶向澱粉樣蛋白前體可減少後期阿爾茨海默氏樣病理。相關論文於2020年11月16日在線發表於《自然—神經科學》。
在可檢測到β-澱粉樣蛋白（Aβ）沉積之前，研究人員在Aβ前體蛋白轉基因小鼠中測試了各種抗體中和Aβ種子的能力。研究人員還使用了不同大小的小鼠和人腦來源的天然Aβ聚集體進行免疫沉澱來表徵不同的抗體識別譜。在澱粉樣前期急性給藥後，至少一種抗體（aducanumab）導致6個月後Aβ沉積和下遊病理的顯著降低。這表明在腦中蛋白質聚集的滯後階段已存在可治療性靶向的致病性Aβ種子。
因此，阿爾茨海默氏病的臨床前階段（目前定義為無臨床症狀的Aβ沉積）可能是病原體種子形成和傳播的較晚表現，目前尚無法在體內進行檢測。
研究人員介紹，Aβ沉積是阿爾茨海默氏病中Aβ聚集相對較晚的結果。當致病性Aβ種子開始形成、繁殖和擴散時，還無法得知，也沒有對其進行生化定義。
附：英文原文
Title: Acute targeting of pre-amyloid seeds in transgenic mice reduces Alzheimer-like pathology later in life
Author: Ruth E. Uhlmann, Christine Rother, Jay Rasmussen, Juliane Schelle, Carina Bergmann, Emily M. Ullrich Gavilanes, Sarah K. Fritschi, Anika Buehler, Frank Baumann, Angelos Skodras, Rawaa Al-Shaana, Natalie Beschorner, Lan Ye, Stephan A. Kaeser, Ulrike Obermller, Sren Christensen, Fredrik Kartberg, Jeffrey B. Stavenhagen, Jens-Ulrich Rahfeld, Holger Cynis, Fang Qian, Paul H. Weinreb, Thierry Bussiere, Lary C. Walker, Matthias Staufenbiel, Mathias Jucker
Issue&Volume: 2020-11-16
Abstract: Amyloid-β (Aβ) deposits are a relatively late consequence of Aβ aggregation in Alzheimer『s disease. When pathogenic Aβ seeds begin to form, propagate and spread is not known, nor are they biochemically defined. We tested various antibodies for their ability to neutralize Aβ seeds before Aβ deposition becomes detectable in Aβ precursor protein-transgenic mice. We also characterized the different antibody recognition profiles using immunoprecipitation of size-fractionated, native, mouse and human brain-derived Aβ assemblies. At least one antibody, aducanumab, after acute administration at the pre-amyloid stage, led to a significant reduction of Aβ deposition and downstream pathologies 6 months later. This demonstrates that therapeutically targetable pathogenic Aβ seeds already exist during the lag phase of protein aggregation in the brain. Thus, the preclinical phase of Alzheimer『s disease—currently defined as Aβ deposition without clinical symptoms—may be a relatively late manifestation of a much earlier pathogenic seed formation and propagation that currently escapes detection in vivo.
DOI: 10.1038/s41593-020-00737-w
Source: https://www.nature.com/articles/s41593-020-00737-w