近日，美国圣犹大儿童研究医院教授Douglas R. Green及其研究小组探明了LC3介导的内吞作用促进β淀粉样蛋白清除并减轻小鼠阿尔茨海默病的神经变性。 这一研究成果于2019年7月25日发表在国际顶尖学术期刊《细胞》上。

在LC3介导的自噬（LANDO)过程中，小组已经鉴定了几种自噬蛋白在LC3与Rab5⁺、clathrin⁺内体结合过程中的一种新的非典型功能，这种内体含有β-淀粉样蛋白。研究发现，在AD小鼠模型中，小胶质细胞中LANDO是免疫介导的聚集物清除和小胶质细胞激活的关键调节器。在骨髓室或特别是小胶质细胞中缺乏LANDO,而不是典型的自噬的小鼠，促炎性细胞因子显著增加，海马体的产生和神经毒性β-淀粉样蛋白水平的增加。这种炎症和β-淀粉样蛋白沉积与反应性微胶质增生和tau高磷酸化有关。LANDO缺陷的AD小鼠表现为加速的神经退行性变、受损的神经元信号和记忆缺陷。研究数据支持小胶质细胞中LANDO在β-淀粉样蛋白沉积引起的神经退行性病变中的保护作用。

据介绍，随着年龄的增长，自噬途径中某些蛋白的表达下降，这可能会影响包括阿尔茨海默症在内的疾病的神经退行性变。

附：英文原文

Title: LC3-Associated Endocytosis Facilitates β-Amyloid Clearance and Mitigates Neurodegeneration in Murine Alzheimer’s Disease

Author: Bradlee L. Heckmann, Brett J.W. Teubner, Bart Tummers, Clifford S. Guy, Stanislav S. Zakharenko, Douglas R. Green

Issue&Volume: Volume 178 Issue 3

Abstract: The expression of some proteins in the autophagy pathway declines with age, which may impact neurodegeneration in diseases, including Alzheimer’s Disease. We have identified a novel non-canonical function of several autophagy proteins in the conjugation of LC3 to Rab5 +, clathrin + endosomes containing β-amyloid in a process of LC3-associated endocytosis (LANDO). We found that LANDO in microglia is a critical regulator of immune-mediated aggregate removal and microglial activation in a murine model of AD. Mice lacking LANDO but not canonical autophagy in the myeloid compartment or specifically in microglia have a robust increase in pro-inflammatory cytokine production in the hippocampus and increased levels of neurotoxic β-amyloid. This inflammation and β-amyloid deposition were associated with reactive microgliosis and tau hyperphosphorylation. LANDO-deficient AD mice displayed accelerated neurodegeneration, impaired neuronal signaling, and memory deficits. Our data support a protective role for LANDO in microglia in neurodegenerative pathologies resulting from β-amyloid deposition.

DOI:https://doi.org/10.1016/j.cell.2019.05.056

Source: https://www.cell.com/cell/fulltext/S0092-8674(19)30627-0#