Zuroff Leah, Daley David, Black Keith L, Koronyo-Hamaoui Maya
Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, 127 S. San Vicente, AHSP A8115, Los Angeles, CA, 90048, USA.
Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
Cell Mol Life Sci. 2017 Jun;74(12):2167-2201. doi: 10.1007/s00018-017-2463-7. Epub 2017 Feb 14.
Deficiency in cerebral amyloid β-protein (Aβ) clearance is implicated in the pathogenesis of the common late-onset forms of Alzheimer's disease (AD). Accumulation of misfolded Aβ in the brain is believed to be a net result of imbalance between its production and removal. This in turn may trigger neuroinflammation, progressive synaptic loss, and ultimately cognitive decline. Clearance of cerebral Aβ is a complex process mediated by various systems and cell types, including vascular transport across the blood-brain barrier, glymphatic drainage, and engulfment and degradation by resident microglia and infiltrating innate immune cells. Recent studies have highlighted a new, unexpected role for peripheral monocytes and macrophages in restricting cerebral Aβ fibrils, and possibly soluble oligomers. In AD transgenic (ADtg) mice, monocyte ablation or inhibition of their migration into the brain exacerbated Aβ pathology, while blood enrichment with monocytes and their increased recruitment to plaque lesion sites greatly diminished Aβ burden. Profound neuroprotective effects in ADtg mice were further achieved through increased cerebral recruitment of myelomonocytes overexpressing Aβ-degrading enzymes. This review summarizes the literature on cellular and molecular mechanisms of cerebral Aβ clearance with an emphasis on the role of peripheral monocytes and macrophages in Aβ removal.
脑淀粉样β蛋白（Aβ）清除功能缺陷与常见晚发型阿尔茨海默病（AD）的发病机制有关。大脑中错误折叠的Aβ积累被认为是其产生与清除失衡的最终结果。这进而可能引发神经炎症、渐进性突触丧失，并最终导致认知衰退。脑Aβ的清除是一个由多种系统和细胞类型介导的复杂过程，包括跨越血脑屏障的血管运输、类淋巴引流，以及常驻小胶质细胞和浸润的固有免疫细胞的吞噬与降解。最近的研究突出了外周单核细胞和巨噬细胞在限制脑Aβ纤维以及可能还有可溶性寡聚体方面的新的、意想不到的作用。在AD转基因（ADtg）小鼠中，单核细胞消融或抑制其向脑内迁移会加剧Aβ病理变化，而血液中单核细胞增多及其向斑块病变部位的募集增加则大大减轻了Aβ负担。通过增加过表达Aβ降解酶的骨髓单核细胞向脑内的募集，在ADtg小鼠中进一步实现了显著的神经保护作用。本综述总结了关于脑Aβ清除的细胞和分子机制的文献，重点关注外周单核细胞和巨噬细胞在Aβ清除中的作用。
