Targeting the APP-Mint2 Protein-Protein Interaction with a Peptide-Based Inhibitor Reduces Amyloid-β Formation.
Targeting the APP-Mint2 Protein-Protein Interaction with a Peptide-Based Inhibitor Reduces Amyloid-β Formation.
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DOI：
10.1021/jacs.0c10696
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发表时间：
2021-01-20
影响因子：
15
通讯作者：
Strømgaard K
中科院分区：
文献类型：
--
作者：
Bartling CRO;Jensen TMT;Henry SM;Colliander AL;Sereikaite V;Wenzler M;Jain P;Maric HM;Harpsøe K;Pedersen SW;Clemmensen LS;Haugaard-Kedström LM;Gloriam DE;Ho A;Strømgaard K
迫切需要能够缓解临床症状并阻止疾病进展的新型治疗方法来治疗阿尔茨海默病（AD）。AD的特征是淀粉样前体蛋白（APP）的连续蛋白水解裂解产生的淀粉样β（Aβ）肽的蓄积。先前的研究报道，Mint 2是一种结合APP和γ-分泌酶复合物的神经元衔接蛋白，影响APP加工和致病性Aβ的形成。然而，关于Mint 2对Aβ生成是否具有促进或抑制作用，存在相互矛盾的结果。在本文中，我们通过对骨架氢键和侧链相互作用的广泛探测来破译APP-Mint 2蛋白质-蛋白质相互作用（PPI）。我们还开发了一种蛋白水解稳定的高亲和力肽，靶向APP-Mint 2相互作用。我们发现，APP结合缺陷型Mint 2变体和细胞渗透性PPI抑制剂均显著降低了AD神经元体外模型中的Aβ42水平。总之，这些发现证明了Mint 2在Aβ形成中的促进作用，遗传和药理学方法的结合表明，靶向Mint 2是降低致病性Aβ水平的有希望的治疗策略。
There is an urgent need for novel therapeutic approaches to treat Alzheimer’s disease (AD) with the ability to both alleviate the clinical symptoms and halt the progression of the disease. AD is characterized by the accumulation of amyloid-β (Aβ) peptides which are generated through the sequential proteolytic cleavage of the amyloid precursor protein (APP). Previous studies reported that Mint2, a neuronal adaptor protein binding both APP and the γ-secretase complex, affects APP processing and formation of pathogenic Aβ. However, there have been contradicting results concerning whether Mint2 has a facilitative or suppressive effect on Aβ generation. Herein, we deciphered the APP-Mint2 protein–protein interaction (PPI) via extensive probing of both backbone H-bond and side-chain interactions. We also developed a proteolytically stable, high-affinity peptide targeting the APP-Mint2 interaction. We found that both an APP binding-deficient Mint2 variant and a cell-permeable PPI inhibitor significantly reduced Aβ42 levels in a neuronal in vitro model of AD. Together, these findings demonstrate a facilitative role of Mint2 in Aβ formation, and the combination of genetic and pharmacological approaches suggests that targeting Mint2 is a promising therapeutic strategy to reduce pathogenic Aβ levels.
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影响因子：
7.7
作者：
Lynagh, Timothy;Flood, Emelie;Pless, Stephan A.
通讯作者：
Pless, Stephan A.
影响因子：
3.5
作者：
Mitchell, Jacqueline C.;Ariff, Belall B.;McLoughlin, Declan M.
通讯作者：
McLoughlin, Declan M.
影响因子：
15
作者：
Bunagan MR;Gao J;Kelly JW;Gai F
通讯作者：
Gai F
DOI：
10.1523/jneurosci.2481-08.2008
发表时间：
2008-12-31
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Ho A;Liu X;Südhof TC
通讯作者：
Südhof TC
影响因子：
15
作者：
Deechongkit, S;Dawson, PE;Kelly, JW
通讯作者：
Kelly, JW