Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND 58203-9037, USA.
J Alzheimers Dis. 2011;25(2):279-93. doi: 10.3233/JAD-2011-101014.
Alzheimer's disease (AD) is an age-associated disease characterized by increased accumulation of extracellular amyloid-β (Aβ) plaques within the brain. Histological examination has also revealed profound microglial activation in diseased brains often in association with these fibrillar peptide aggregates. The paradoxical presence of increased, reactive microglia yet accumulating extracellular debris suggests that these cells may be phagocytically compromised during disease. Prior work has demonstrated that primary microglia from adult mice are unable to phagocytose fibrillar Aβ1-42 in vitro when compared to microglia cultured from early postnatal animals. These data suggest that microglia undergo an age-associated decrease in microglial ability to interact with Aβ fibrils. In order to better define a temporal profile of microglia-Aβ interaction, acutely isolated, rather than cultured, microglia from 2 month, 6 month, and postnatal day 0 C57BL/6 mice were compared. Postnatal day 0 microglia demonstrated a CD47 dependent ability to phagocytose Aβ fibrils that was lost by 6 months. This corresponded with the ability of postnatal day 0 but not adult microglia to decrease Aβ immunoreactive plaque load from AD sections in vitro. In spite of limited Aβ uptake ability, adult microglia had functional phagocytic uptake of bacterial bioparticles and demonstrated the ability to adhere to both Aβ plaques and in vitro fibrillized Aβ. These data demonstrate a temporal profile of specifically Aβ-microglia interaction with a critical developmental period at 6 months in which cells remain able to interact with Aβ fibrils but lose their ability to phagocytose it.
阿尔茨海默病（AD）是一种与年龄相关的疾病，其特征是大脑内细胞外淀粉样β（Aβ）斑块的积累增加。组织学检查还显示，在患病大脑中存在深刻的小胶质细胞激活，通常与这些纤维状肽聚集物有关。存在增加的、反应性的小胶质细胞而同时积累细胞外碎片的矛盾现象表明，这些细胞在疾病期间可能在吞噬作用方面受到损害。先前的工作已经表明，与从小鼠早期培养的小胶质细胞相比，成年小鼠的原代小胶质细胞在体外无法吞噬纤维状 Aβ1-42。这些数据表明，小胶质细胞在与 Aβ 纤维相互作用方面随着年龄的增长而降低。为了更好地定义小胶质细胞与 Aβ 相互作用的时间谱，比较了来自 2 个月、6 个月和出生后 0 天 C57BL/6 小鼠的急性分离而非培养的小胶质细胞。出生后 0 天的小胶质细胞表现出依赖 CD47 的吞噬 Aβ 纤维的能力，该能力在 6 个月时丧失。这与出生后 0 天的小胶质细胞但不是成年小胶质细胞能够减少体外 AD 切片中 Aβ 免疫反应性斑块负荷的能力相对应。尽管小胶质细胞摄取 Aβ 的能力有限，但成年小胶质细胞具有细菌生物颗粒的功能性吞噬摄取能力，并表现出与 Aβ 斑块和体外纤维状 Aβ 粘附的能力。这些数据显示了 Aβ-小胶质细胞相互作用的时间谱，在 6 个月时有一个关键的发育时期，在此期间细胞仍然能够与 Aβ 纤维相互作用，但失去了吞噬它的能力。
