Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, Illinois, USA.
Am J Pathol. 2011 Sep;179(3):1095-103. doi: 10.1016/j.ajpath.2011.05.045. Epub 2011 Jul 19.
The accumulation of β-amyloid protein (Aβ) in the brain is thought to be a primary etiologic event in Alzheimer's disease (AD). Fibrillar Aβ plaques, a hallmark of AD abnormality, are closely associated with activated microglia. Activated microglia have contradictory roles in the pathogenesis of AD, being either neuroprotective (by clearing harmful Aβ and repairing damaged tissues) or neurotoxic (by producing proinflammatory cytokines and reactive oxygen species). Aβ aggregates can activate microglia by interacting with multiple toll-like receptors (TLRs), the pattern-recognition receptors of the innate immune system. Because the adapter protein MyD88 is essential for the downstream signaling of all TLRs, except TLR3, we investigated the effects of MyD88 deficiency (MyD88(-/-)) on Aβ accumulation and microglial activation in an AD mouse model. MyD88 deficiency decreased Aβ load and microglial activation in the brain. The decrease in Aβ load in an MyD88(-/-) AD mouse model was associated with increased and decreased protein expression of apolipoprotein E (apoE) and CX3CR1, respectively, compared with that in an MyD88 wild-type AD mouse model. These results suggest that MyD88 deficiency may reduce Aβ load by enhancing the phagocytic capability of microglia through fractalkine (the ligand of CX3CR1) signaling and by promoting apoE-mediated clearance of Aβ from the brain. These findings also suggest that chronic inflammatory responses induced by Aβ accumulation via the MyD88-dependent signaling pathway exacerbate β-amyloidosis in AD.
β-淀粉样蛋白（Aβ）在大脑中的积累被认为是阿尔茨海默病（AD）的主要病因。纤维状 Aβ 斑块是 AD 异常的标志，与活化的小胶质细胞密切相关。活化的小胶质细胞在 AD 的发病机制中具有矛盾的作用，既具有神经保护作用（通过清除有害的 Aβ 和修复受损组织），也具有神经毒性作用（通过产生促炎细胞因子和活性氧）。Aβ 聚集物可以通过与多种 Toll 样受体（TLRs）相互作用来激活小胶质细胞，TLRs 是先天免疫系统的模式识别受体。由于适配器蛋白 MyD88 是除 TLR3 之外所有 TLR 下游信号转导所必需的，因此我们研究了 MyD88 缺失（MyD88(-/-)）对 AD 小鼠模型中 Aβ 积累和小胶质细胞激活的影响。MyD88 缺失可减少大脑中的 Aβ 负荷和小胶质细胞激活。与 MyD88 野生型 AD 小鼠模型相比，MyD88(-/-)AD 小鼠模型中的 Aβ 负荷减少与载脂蛋白 E（apoE）和 CX3CR1 的蛋白表达分别增加和减少有关。这些结果表明，MyD88 缺失可能通过 fractalkine（CX3CR1 的配体）信号增强小胶质细胞的吞噬能力，并通过促进 apoE 介导的 Aβ 从大脑中的清除来减少 Aβ 负荷。这些发现还表明，通过 MyD88 依赖性信号通路累积 Aβ 引起的慢性炎症反应会加剧 AD 中的β-淀粉样蛋白沉积。
