Pharmacological intervention in a transgenic mouse model improves Alzheimer's-associated pathological phenotype: Involvement of proteasome activation.
Pharmacological intervention in a transgenic mouse model improves Alzheimer's-associated pathological phenotype: Involvement of proteasome activation.
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DOI：
10.1016/j.freeradbiomed.2020.11.038
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发表时间：
2021-01
影响因子：
7.4
通讯作者：
Gonos ES
中科院分区：
文献类型：
--
作者：
Mladenovic Djordjevic AN;Kapetanou M;Loncarevic-Vasiljkovic N;Todorovic S;Athanasopoulou S;Jovic M;Prvulovic M;Taoufik E;Matsas R;Kanazir S;Gonos ES
阿尔茨海默病（AD）是世界范围内最常见的痴呆症形式，其特征是各种认知和非认知功能的进行性下降。淀粉样β蛋白级联假说将淀粉样β蛋白聚集体的形成置于导致神经变性的复杂病理级联的首位，因此AD可能被认为是一种蛋白质错误折叠疾病。泛素蛋白酶体系统（Ubiquitin Proteasome System， UPS）是主要的蛋白质降解机制，在维持蛋白质平衡中起着重要作用，已被认为是延迟和/或减缓以蛋白质积累/聚集为特征的神经退行性疾病进展的假定治疗靶点。本研究的目的是测试体内蛋白酶体的激活是否可以减轻AD的病理。具体来说，通过在5xFAD转基因AD小鼠模型中使用两种具有互补的蛋白酶体激活模式和记录的抗氧化和氧化还原调节特性的化合物，我们改善了许多AD相关的缺陷。在蛋白酶体激活后不久，我们检测到显著减少的β淀粉样蛋白负荷与改善的运动功能、减少的焦虑和虚弱水平相关。本质上，据我们所知，这是第一个证明蛋白酶体及其下游作用的双重激活的报告。总之，这些发现为蛋白酶体介导的蛋白水解增强的未来治疗潜力开辟了新的方向。
Alzheimer’s disease (AD) is the most common form of dementia worldwide, characterized by a progressive decline in a variety of cognitive and non-cognitive functions. The amyloid beta protein cascade hypothesis places the formation of amyloid beta protein aggregates on the first position in the complex pathological cascade leading to neurodegeneration, and therefore AD might be considered to be a protein-misfolding disease. The Ubiquitin Proteasome System (UPS), being the primary protein degradation mechanism with a fundamental role in the maintenance of proteostasis, has been identified as a putative therapeutic target to delay and/or to decelerate the progression of neurodegenerative disorders that are characterized by accumulated/aggregated proteins. The purpose of this study was to test if the activation of proteasome in vivo can alleviate AD pathology. Specifically by using two compounds with complementary modes of proteasome activation and documented antioxidant and redox regulating properties in the 5xFAD transgenic mice model of AD, we ameliorated a number of AD related deficits. Shortly after proteasome activation we detected significantly reduced amyloid-beta load correlated with improved motor functions, reduced anxiety and frailty level. Essentially, to our knowledge this is the first report to demonstrate a dual activation of the proteasome and its downstream effects. In conclusion, these findings open up new directions for future therapeutic potential of proteasome-mediated proteolysis enhancement.
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影响因子：
2.9
作者：
Cecarini, Valentina;Bonfili, Laura;Eleuteri, Anna Maria
通讯作者：
Eleuteri, Anna Maria
影响因子：
4.8
作者：
Chondrogianni, Niki;Georgila, Konstantina;Gonos, Efstathios S.
通讯作者：
Gonos, Efstathios S.
影响因子：
4.3
作者：
Buchman AS;Bennett DA
通讯作者：
Bennett DA
DOI：
10.1002/agm2.12058
发表时间：
2019-03-01
期刊：
Aging medicine (Milton (N.S.W))
影响因子：
--
作者：
Bisset, Elise S;Howlett, Susan E
通讯作者：
Howlett, Susan E
影响因子：
5.3
作者：
Bedford, Lynn;Hay, David;Mayer, R. John
通讯作者：
Mayer, R. John