Significance of cytosolic cathepsin D in Alzheimer's disease pathology: Protective cellular effects of PLGA nanoparticles against β-amyloid-toxicity.
Significance of cytosolic cathepsin D in Alzheimer's disease pathology: Protective cellular effects of PLGA nanoparticles against β-amyloid-toxicity.
复制标题
DOI：
10.1111/nan.12647
复制
发表时间：
2020-12
影响因子：
5
通讯作者：
Kar S
中科院分区：
文献类型：
--
作者：
Wang Y;Wu Q;Anand BG;Karthivashan G;Phukan G;Yang J;Thinakaran G;Westaway D;Kar S
有证据表明，淀粉样蛋白β（Aβ）肽在阿尔茨海默病（AD）的发展过程中的神经元变性中起重要作用，阿尔茨海默病是影响老年人的痴呆的普遍原因。内体-溶酶体系统作为Aβ代谢的主要位点，已显示在AD脑的脆弱神经元中表现出异常，反映为溶酶体酶（包括组织蛋白酶D（CatD））的水平/表达增强。目前，CatD在AD病理学中选择性神经元脆弱性的意义尚不清楚。我们评估了CatD在Aβ处理的培养物、转基因AD小鼠模型（即，5xFAD）和死后AD脑样品。我们的研究结果表明，Aβ1-42诱导的皮质培养神经元毒性与溶酶体完整性受损、羰基化蛋白水平升高和tau蛋白磷酸化相关。在暴露于Aβ肽后，培养的神经元中CatD的细胞和胞质水平/活性也升高。此外，我们观察到CatD细胞和亚细胞水平/活性在5xFAD小鼠和死后AD脑的受影响皮质中增加，但在未受影响的小脑中没有增加。有趣的是，用靶向溶酶体系统的纳米颗粒PLGA处理培养的神经元，通过降低羰基化蛋白水平、tau磷酸化和CatD的水平/分布/活性来减弱Aβ毒性。我们的研究表明，增加胞浆水平/活性的CatD发挥重要作用，在确定神经元的脆弱性在AD。此外，天然PLGA可以通过恢复溶酶体膜完整性来保护神经元免受Aβ毒性，从而表明其在减轻AD中的意义。
Evidence suggests that amyloid β (Aβ) peptides play an important role in the degeneration of neurons during the development of Alzheimer’s disease (AD), the prevalent cause of dementia affecting the elderly. The endosomal-lysosomal system, which acts as a major site for Aβ metabolism, has been shown to exhibit abnormalities in vulnerable neurons of the AD brain, reflected by enhanced levels/expression of lysosomal enzymes including cathepsin D (CatD). At present, the implication of CatD in selective neuronal vulnerability in AD pathology remains unclear. We evaluated the role of CatD in the degeneration of neurons in Aβ-treated cultures, transgenic AD mouse model (i.e., 5xFAD) and post-mortem AD brain samples. Our results showed that Aβ1–42-induced toxicity in cortical cultured neurons is associated with impaired lysosomal integrity, enhanced levels of carbonylated proteins and tau phosphorylation. The cellular and cytosolic levels/activity of CatD are also elevated in cultured neurons following exposure to Aβ peptide. Additionally, we observed that CatD cellular and subcellular levels/activity are increased in the affected cortex, but not in the unaffected cerebellum, of 5xFAD mice and post-mortem AD brains. Interestingly, treatment of cultured neurons with nanoparticles PLGA, which targets lysosomal system, attenuated Aβ toxicity by reducing the levels of carbonylated proteins, tau phosphorylation and the level/distribution/activity of CatD. Our study reveals that increased cytosolic level/activity of CatD play an important role in determining neuronal vulnerability in AD. Additionally, native PLGA can protect neurons against Aβ toxicity by restoring lysosomal membrane integrity, thus signifying its implication in attenuating AD.
登录
查看更多内容
影响因子：
6
作者：
Fujikawa, Denson G.
通讯作者：
Fujikawa, Denson G.
影响因子：
3.3
作者：
Baysal, Ipek;Ucar, Gulberk;Yabanoglu-Ciftci, Samiye
通讯作者：
Yabanoglu-Ciftci, Samiye
影响因子：
4.2
作者：
Amritraj, A.;Hawkes, C.;Kar, S.
通讯作者：
Kar, S.
影响因子：
4.8
作者：
Amritraj, Asha;Wang, Yanlin;Kar, Satyabrata
通讯作者：
Kar, Satyabrata
影响因子：
4.7
作者：
Dawkins E;Small DH
通讯作者：
Small DH