An isogenic panel of single App knock-in mouse models of Alzheimer’s disease confers differential profiles of β-secretase inhibition and endosomal abnormalities
An isogenic panel of single App knock-in mouse models of Alzheimer’s disease confers differential profiles of β-secretase inhibition and endosomal abnormalities
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阿尔茨海默病的单 App 敲入小鼠模型的同基因组赋予了 β-分泌酶抑制和内体异常的差异特征
DOI：
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Hiroki Sasaguri
中科院分区：
文献类型：
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作者：
Naoto Watamura;Kaori Sato;G. Shiihashi;A. Iwasaki;Naoko Kamano;Mika Takahashi;Misaki Sekiguchi;N. Yamazaki;Ryo Fujioka;K. Nagata;Shoko Hashimoto;T. Saito;T. Ohshima;T. Saido;Hiroki Sasaguri
我们先前开发了阿尔茨海默病（AD）的单个App敲入小鼠模型，其具有瑞典和拜罗伊特/伊比利亚突变，具有或不具有北极突变（AppNL-G-F和AppNL-F小鼠）。这些模型显示了随着年龄的增长，淀粉样β肽（Aβ）病理学、神经炎症和认知障碍的发展。我们现在已经产生了没有Swedish突变的App敲入小鼠（AppG-F小鼠）和一些额外的突变体，以解决以下两个问题：[1] Swedish突变是否影响β-分泌酶抑制剂在体内的作用模式？[2]β-分泌酶（CTF-β）产生的淀粉样前体蛋白（APP）C端片段的数量是否影响了先前报道的内体性质以及其他病理事件？6 - 8月龄的AppG-F小鼠表现出Aβ病理学，并伴有小胶质细胞和星形胶质细胞活化。我们发现，β-分泌酶抑制剂verubecestat可抑制AppG-F小鼠的Aβ生成，但在AppNL-G-F小鼠中则不然，这表明AppG-F小鼠更适合β-分泌酶抑制的临床前研究，因为大多数AD患者不携带Swedish突变。我们还发现，由各种App敲入突变体产生的CTF-β的量未能与内体改变或增大相关，这意味着CTF-β、内体异常或两者不太可能在AD发病机制中起主要作用。这是有史以来第一个描述的AD小鼠模型，其在不存在瑞典突变并且不依赖于过表达范例的情况下再现了大脑中的淀粉样蛋白病理学。因此，不同App基因敲入小鼠品系之间的实验比较将可能为我们理解AD的病因提供新的见解。
We previously developed single App knock-in mouse models of Alzheimer’s disease (AD) that harbor the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation (AppNL- G-F and AppNL-F mice). These models showed the development of amyloid β peptide (Aβ) pathology, neuroinflammation and cognitive impairment with aging. We have now generated App knock-in mice devoid of the Swedish mutations (AppG-F mice) and some additional mutants to address the following two questions: [1] Do the Swedish mutations influence the mode of β-secretase inhibitor action in vivo? [2] Does the quantity of C-terminal fragment of amyloid precursor protein (APP) generated by β-secretase (CTF-β) affect endosomal properties as previously reported as well as other pathological events? Aβ pathology was exhibited by AppG-F mice from 6 to 8 months of age, and was accompanied by microglial and astrocyte activation. We found that a β-secretase inhibitor, verubecestat, inhibited Aβ production in AppG-F mice, but not in AppNL-G-F mice, indicating that the AppG-F mice are more suitable for preclinical studies of β-secretase inhibition given that most AD patients do not carry Swedish mutations. We also found that the quantity of CTF-β generated by various App knock-in mutants failed to correlate with endosomal alterations or enlargement, implying that CTF-β, endosomal abnormalities, or both are unlikely to play a major role in AD pathogenesis. This is the first AD mouse model ever described that recapitulates amyloid pathology in the brain without the presence of Swedish mutations and without relying on the overexpression paradigm. Thus, experimental comparisons between different App knock-in mouse lines will potentially provide new insights into our understanding of the etiology of AD.
影响因子：
15.9
作者：
Xu, Wei;Weissmiller, April M.;Wu, Chengbiao
通讯作者：
Wu, Chengbiao
影响因子：
8.8
作者：
Anna Pensalfini;Seonil Kim;Shivakumar Subbanna;C. Bleiwas;C. Goulbourne;Philip H. Stavrides;Ying Jiang;Ju-Hyun Lee;Sandipkumar Darji;M. Pawlik;Chunfeng Huo;James Peddy;M. Berg;J. Smiley;B. Basavarajappa;R. Nixon
通讯作者：
Anna Pensalfini;Seonil Kim;Shivakumar Subbanna;C. Bleiwas;C. Goulbourne;Philip H. Stavrides;Ying Jiang;Ju-Hyun Lee;Sandipkumar Darji;M. Pawlik;Chunfeng Huo;James Peddy;M. Berg;J. Smiley;B. Basavarajappa;R. Nixon
影响因子：
8.8
作者：
Woodruff G;Reyna SM;Dunlap M;Van Der Kant R;Callender JA;Young JE;Roberts EA;Goldstein LS
通讯作者：
Goldstein LS