Richard Karine L, Filali Mohammed, Préfontaine Paul, Rivest Serge
Laboratory of Molecular Endocrinology, Centre hospitalier de l'Université Laval Research Center, Department of Anatomy and Physiology, Laval University, Québec, Canada.
J Neurosci. 2008 May 28;28(22):5784-93. doi: 10.1523/JNEUROSCI.1146-08.2008.
Microglia are the immune cells of the brain, they are activated in the brain of Alzheimer's disease (AD) patients and mouse models of AD, and they express the innate immune receptor toll-like receptor 2 (TLR2). The present study investigated role of this receptor in the progression of AD-like pathologies. Here we show that amyloid beta (A beta) stimulates TLR2 expression in a small proportion of microglia. We then generated triple transgenic mice that are deficient in TLR2 from mice that harbor a mutant human presenelin 1 and a chimeric mouse/human amyloid precursor protein (APP) genes. TLR2 deficiency accelerated spatial and contextual memory impairments, which correlated with increased levels of A beta(1-42) and transforming growth factor beta1 in the brain. NMDA receptors 1 and 2A expression levels were also lower in the hippocampus of APP-TLR2(-/-) mice. Gene therapy in cells of the bone marrow using lentivirus constructs expressing TLR2 rescued the cognitive impairment of APP-TLR2(-/-) mice. Indeed, lenti-green fluorescent protein/TLR2 treatment had beneficial effects by restoring the memory consolidation process disrupted by TLR2 deficiency in APP mice. These data suggest that TLR2 acts as an endogenous receptor for the clearance of toxic A beta by bone-marrow-derived immune cells. The cognitive decline is markedly accelerated in a context of TLR2 deficiency. Upregulating this innate immune receptor may then be considered as a potential new powerful therapeutic approach for AD.
小胶质细胞是大脑的免疫细胞，在阿尔茨海默病（AD）患者及AD小鼠模型的大脑中被激活，且它们表达天然免疫受体Toll样受体2（TLR2）。本研究调查了该受体在AD样病理进展中的作用。在此我们表明，β淀粉样蛋白（Aβ）在一小部分小胶质细胞中刺激TLR2表达。然后我们从携带突变型人类早老素1和嵌合型小鼠/人类淀粉样前体蛋白（APP）基因的小鼠中培育出TLR2缺陷的三转基因小鼠。TLR2缺陷加速了空间和情境记忆损害，这与大脑中Aβ（1-42）和转化生长因子β1水平升高相关。APP-TLR2（-/-）小鼠海马中的N-甲基-D-天冬氨酸受体1和2A表达水平也较低。使用表达TLR2的慢病毒构建体对骨髓细胞进行基因治疗挽救了APP-TLR2（-/-）小鼠的认知障碍。实际上，慢病毒绿色荧光蛋白/TLR2治疗通过恢复APP小鼠中因TLR2缺陷而破坏的记忆巩固过程产生了有益效果。这些数据表明，TLR2作为骨髓源性免疫细胞清除有毒Aβ的内源性受体。在TLR2缺陷的情况下，认知衰退明显加速。上调这种天然免疫受体可能因此被视为AD一种潜在的强有力的新治疗方法。
