LMP2 Inhibitors as a Potential Treatment for Alzheimer's Disease
LMP2 Inhibitors as a Potential Treatment for Alzheimer's Disease
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DOI：
10.1021/acs.jmedchem.0c00416
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发表时间：
2020-04-09
影响因子：
7.3
通讯作者：
Kim, Kyung Bo
中科院分区：
文献类型：
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作者：
Bhattarai, Deepak;Lee, Min Jae;Kim, Kyung Bo
免疫蛋白酶体（iP）是一种可诱导的蛋白酶体变体，含有三个免疫亚基，低分子量多肽-2（LMP2）、多催化内肽酶复合物亚基-1和低分子量多肽-7（LMP7），参与炎症反应的多个方面。我们最近报道，YU102，一种iP亚基LMP2和组成性蛋白酶体催化亚基β 1的双重抑制剂，改善阿尔茨海默病（AD）小鼠模型的认知障碍，与淀粉样蛋白沉积无关。为了研究抑制LMP2是否足以改善AD小鼠的认知功能，我们制备了37种YU102类似物，并鉴定了一种有效的LMP2抑制剂DB-310（28）（IC50：80.6 nM），其在过表达ABCB 1转运蛋白的细胞中具有改善的选择性和渗透性。我们表明，DB-310诱导抑制小胶质细胞中IL-1 α的产生，并改善AD的Tg2576转基因小鼠模型的认知功能。这项研究支持LMP2的抑制是治疗AD的一种有前途的治疗策略。
The immunoproteasome (iP), an inducible proteasome variant harboring three immunosubunits, low molecular mass polypeptide-2 (LMP2), multicatalytic endopeptidase complex subunit-1, and low molecular mass polypeptide-7 (LMP7), is involved in multiple facets of inflammatory responses. We recently reported that YU102, a dual inhibitor of the iP subunit LMP2 and the constitutive proteasome catalytic subunit beta 1, ameliorates cognitive impairments in mouse models of Alzheimer's disease (AD) independently of amyloid deposits. To investigate whether inhibition of LMP2 is sufficient to improve the cognitive functions of AD mice, here we prepared 37 YU102 analogues and identified a potent LMP2 inhibitor DB-310 (28) (IC50: 80.6 nM) with improved selectivity and permeability in cells overexpressing ABCB1 transporters. We show that DB-310 induces suppression of IL-1 alpha production in microglia cells and improves cognitive functions in the Tg2576 transgenic mouse model of AD. This study supports that inhibition of LMP2 is a promising therapeutic strategy for treatment of AD.