Division of Chemical Biology & BioTechnology, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Singapore.
IMDEA-Food Research Institute, +Pec Proteomics, Campus of International Excellence UAM+CSIC, Old Cantoblanco Hospital, 8 Crta. Canto Blanco, 28049, Madrid, Spain.
Alzheimers Res Ther. 2020 May 8;12(1):54. doi: 10.1186/s13195-020-00623-4.
The contributions of brain intercellular communication mechanisms, specifically extracellular vesicles (EV), to the progression of Alzheimer's disease (AD) remain poorly understood.
Here, we investigated the role(s) of brain EV in the progressive course of AD through unbiased proteome-wide analyses of temporal lobe-derived EV and proteome-label quantitation of complementary remaining brain portions. Furthermore, relevant proteins identified were further screened by multiple reaction monitoring.
Our data indicate that EV biogenesis was altered during preclinical AD with the genesis of a specific population of EV containing MHC class-type markers. The significant presence of the prion protein PrP was also manifested in these brain vesicles during preclinical AD. Similarly, sequestration of amyloid protein APP in brain EV coincided with the observed PrP patterns. In contrast, active incorporation of the mitophagy protein GABARAP in these brain vesicles was disrupted as AD progressed. Likewise, disrupted incorporation of LAMP1 in brain EV was evident from the initial manifestation of AD clinical symptoms, although the levels of the protein remained significantly upregulated in the temporal lobe of diseased brains.
Our findings indicate that impaired autophagy in preclinical AD coincides with the appearance of proinflammatory and neuropathological features in brain extracellular vesicles, facts that moderately remain throughout the entire AD progression. Thus, these data highlight the significance of brain EV in the establishment of AD neuropathology and represent a further leap toward therapeutic interventions with these vesicles in human dementias.
脑细胞间通讯机制,特别是细胞外囊泡(EV),对阿尔茨海默病(AD)进展的贡献仍知之甚少。
在这里,我们通过对颞叶来源的 EV 进行无偏全蛋白质组分析和对互补的剩余脑部分进行蛋白质组标记定量,研究了脑 EV 在 AD 进行性病程中的作用。此外,还通过多重反应监测进一步筛选了相关蛋白。
我们的数据表明,在 AD 的临床前阶段,EV 的生物发生发生了改变,产生了含有 MHC 类标记物的特定 EV 群体。在这些脑囊泡中也明显存在朊病毒蛋白 PrP。同样,在 AD 的临床前阶段,APP 淀粉样蛋白在脑 EV 中的隔离与观察到的 PrP 模式一致。相反,随着 AD 的进展,GABARAP 等促凋亡蛋白在这些脑囊泡中的主动掺入被破坏。同样,LAMP1 在脑 EV 中的掺入被破坏,从 AD 临床症状的最初表现就可以明显看出,尽管该蛋白在患病大脑的颞叶中仍保持显著上调。
我们的发现表明,AD 临床前阶段的自噬受损与脑细胞外囊泡中促炎和神经病理学特征的出现相吻合,这些特征在整个 AD 进展过程中都存在。因此,这些数据强调了脑 EV 在 AD 神经病理学建立中的重要性,并代表了朝着用这些囊泡进行人类痴呆症治疗干预的又一飞跃。