Research School of Biology, and the Medical School, Australian National University, Canberra, ACT, Australia.
School of Pharmacy, Faculty of Medicine and Health, University of Sydney, NSW, Australia.
FEBS Lett. 2020 Dec;594(23):4076-4084. doi: 10.1002/1873-3468.13951. Epub 2020 Oct 20.
The levels of amyloid peptides in the brain are regulated by a clearance pathway from neurons to the blood-brain barrier. The first step is thought to involve diffusion from the plasma membrane to the interstitium. However, amyloid peptides are hydrophobic and avidly intercalate within membranes. The ABC transporter P-glycoprotein is implicated in the clearance of amyloid peptides across the blood-brain, but its role at neurons is undetermined. We here propose that P-glycoprotein mediates 'exit' of amyloid peptides from neurons. Indeed, amyloid peptides have physicochemical similarities to substrates of P-glycoprotein, but their larger size represents a conundrum. This review probes the plausibility of a mechanism for amyloid peptide transport by P-glycoprotein exploiting evolving biochemical and structural models.
脑内淀粉样肽的水平受从神经元到血脑屏障的清除途径调控。人们认为第一步涉及从质膜扩散到细胞间隙。然而，淀粉样肽具有疏水性，并且在膜内强烈嵌入。ABC 转运蛋白 P-糖蛋白参与了血脑内淀粉样肽的清除，但它在神经元中的作用尚未确定。我们在此提出 P-糖蛋白介导淀粉样肽从神经元“排出”。事实上，淀粉样肽在物理化学性质上与 P-糖蛋白的底物相似，但它们的更大尺寸是一个难题。本综述探讨了利用不断发展的生化和结构模型，P-糖蛋白转运淀粉样肽的机制的合理性。
