Preclinical validation of a potent γ-secretase modulator for Alzheimer's disease prevention.
Preclinical validation of a potent γ-secretase modulator for Alzheimer's disease prevention.
复制标题
DOI：
10.1084/jem.20202560
复制
发表时间：
2021-04-05
期刊：
影响因子：
--
通讯作者：
Wagner SL
中科院分区：
文献类型：
--
作者：
Rynearson KD;Ponnusamy M;Prikhodko O;Xie Y;Zhang C;Nguyen P;Hug B;Sawa M;Becker A;Spencer B;Florio J;Mante M;Salehi B;Arias C;Galasko D;Head BP;Johnson G;Lin JH;Duddy SK;Rissman RA;Mobley WC;Thinakaran G;Tanzi RE;Wagner SL
GSM通过与γ-分泌酶结合并改变外肽酶样加工，优先降低易聚集Aβ42肽的水平。Rynearson等人证明了晚期GSM在转基因脑淀粉样变性小鼠模型中稳健地降低物种间Aβ42水平并改变发病机制的能力。已经开发了一种有效的γ-分泌酶调节剂（GSM），以避免与γ-分泌酶抑制剂（GSI）相关的问题，并可能用于早发性家族性阿尔茨海默病（EOFAD）的一级预防。与GSI不同，GSMs不抑制γ-分泌酶活性，而是变构调节γ-分泌酶，减少Aβ42的净产生，并在较小程度上减少Aβ40的净产生，同时增加Aβ38和Aβ37的产生。该GSM在多个物种的急性、亚慢性和慢性研究中表现出强大的时间和剂量依赖性功效，包括转基因小鼠模型的一级和二级预防研究。基于无明显不良作用水平（NOAEL）下的全身暴露量（AUC）与50%有效AUC或AUC effective（将大鼠脑中Aβ42水平降低50%所需的全身暴露量）的比较，GSM在大鼠中显示出>40倍的安全范围。
GSMs preferentially attenuate levels of the aggregation-prone Aβ42 peptide by binding to the γ-secretase enzyme and altering exopeptidase-like processing. Rynearson et al. demonstrate the ability of an advanced-stage GSM to robustly attenuate Aβ42 levels across species and modify pathogenesis in a transgenic cerebral amyloidosis mouse model. A potent γ-secretase modulator (GSM) has been developed to circumvent problems associated with γ-secretase inhibitors (GSIs) and to potentially enable use in primary prevention of early-onset familial Alzheimer’s disease (EOFAD). Unlike GSIs, GSMs do not inhibit γ-secretase activity but rather allosterically modulate γ-secretase, reducing the net production of Aβ42 and to a lesser extent Aβ40, while concomitantly augmenting production of Aβ38 and Aβ37. This GSM demonstrated robust time- and dose-dependent efficacy in acute, subchronic, and chronic studies across multiple species, including primary and secondary prevention studies in a transgenic mouse model. The GSM displayed a >40-fold safety margin in rats based on a comparison of the systemic exposure (AUC) at the no observed adverse effect level (NOAEL) to the 50% effective AUC or AUCeffective, the systemic exposure required for reducing levels of Aβ42 in rat brain by 50%.
登录
查看更多内容
影响因子：
158.5
作者：
MABUCHI, H;HABA, T;TAKEDA, R
通讯作者：
TAKEDA, R
影响因子：
9.9
作者：
McDade, Eric;Wang, Guoqiao;Bateman, Randall J.
通讯作者：
Bateman, Randall J.
影响因子：
29
作者：
Liu, Qing;Waltz, Shannon;Woodruff, Grace;Ouyang, Joe;Israel, Mason A.;Herrera, Cheryl;Sarsoza, Floyd;Tanzi, Rudolph E.;Koo, Edward H.;Ringman, John M.;Goldstein, Lawrence S. B.;Wagner, Steven L.;Yuan, Shauna H.
通讯作者：
Yuan, Shauna H.
DOI：
10.1056/nejmoa1706441
发表时间：
2018-05-03
期刊：
The New England journal of medicine
影响因子：
--
作者：
Egan MF;Kost J;Tariot PN;Aisen PS;Cummings JL;Vellas B;Sur C;Mukai Y;Voss T;Furtek C;Mahoney E;Harper Mozley L;Vandenberghe R;Mo Y;Michelson D
通讯作者：
Michelson D
影响因子：
158.5
作者：
Egan, Michael F.;Kost, James;Michelson, David
通讯作者：
Michelson, David