Department of Anatomy and Neurosciences, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands.
School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK.
Cells. 2022 Jan 24;11(3):389. doi: 10.3390/cells11030389.
Amyloid-beta (Aβ) deposition in the brain is closely linked with the development of Alzheimer's disease (AD). Unfortunately, therapies specifically targeting Aβ deposition have failed to reach their primary clinical endpoints, emphasizing the need to broaden the search strategy for alternative targets/mechanisms. Transglutaminase-2 (TG2) catalyzes post-translational modifications, is present in AD lesions and interacts with AD-associated proteins. However, an unbiased overview of TG2 interactors is lacking in both control and AD brain. Here we aimed to identify these interactors using a crossbreed of the AD-mimicking APP23 mouse model with wild type and TG2 knock-out (TG2) mice. We found that absence of TG2 had no (statistically) significant effect on Aβ pathology, soluble brain levels of Aβ and Aβ, and mRNA levels of TG family members compared to APP23 mice at 18 months of age. Quantitative proteomics and network analysis revealed a large cluster of TG2 interactors involved in synaptic transmission/assembly and cell adhesion in the APP23 brain typical of AD. Comparative proteomics of wild type and TG2 brains revealed a TG2-linked pathological proteome consistent with alterations in both pathways. Our data show that TG2 deletion leads to considerable network alterations consistent with a TG2 role in (dys)regulation of synaptic transmission and cell adhesion in APP23 brains.
脑内淀粉样蛋白-β（Aβ）沉积与阿尔茨海默病（AD）的发展密切相关。不幸的是，专门针对 Aβ 沉积的治疗方法未能达到其主要临床终点，这强调了需要扩大对替代靶标/机制的搜索策略。转谷氨酰胺酶-2（TG2）催化翻译后修饰，存在于 AD 病变中，并与 AD 相关蛋白相互作用。然而，在对照和 AD 脑中，缺乏对 TG2 相互作用物的无偏见概述。在这里，我们使用 AD 模拟 APP23 小鼠模型与野生型和 TG2 敲除（TG2）小鼠的杂交体来确定这些相互作用物。我们发现，与 APP23 小鼠相比，18 个月时，TG2 的缺失对 Aβ 病理学、可溶性脑 Aβ 水平和 TG 家族成员的 mRNA 水平没有（统计学上）显著影响。定量蛋白质组学和网络分析显示，APP23 脑内存在一大簇与突触传递/组装和细胞黏附相关的 TG2 相互作用物，这是 AD 的典型特征。野生型和 TG2 脑的比较蛋白质组学揭示了与两条通路改变一致的 TG2 相关病理蛋白质组。我们的数据表明，TG2 缺失导致相当大的网络改变，这与 TG2 在 APP23 脑中（失调）调节突触传递和细胞黏附的作用一致。
