Induction of toll-like receptor 9 signaling as a method for ameliorating Alzheimer's disease-related pathology.
Induction of toll-like receptor 9 signaling as a method for ameliorating Alzheimer's disease-related pathology.
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DOI：
10.1523/jneurosci.5715-08.2009
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发表时间：
2009-02-11
期刊：
影响因子：
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通讯作者：
Wisniewski T
中科院分区：
文献类型：
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作者：
Scholtzova H;Kascsak RJ;Bates KA;Boutajangout A;Kerr DJ;Meeker HC;Mehta PD;Spinner DS;Wisniewski T
阿尔茨海默病(AD)的发病机制被认为与淀粉样蛋白沉积和有毒低聚物中淀粉样蛋白(Aβ，Aβ)的积聚有关。免疫调节是一种将平衡从Aβ蓄积转移到清除的有效手段；然而，过度的细胞介导性炎症和脑微出血是这种方法可能发生的两种毒性形式。到目前为止，疫苗接种研究主要针对适应性免疫系统。在本研究中，我们通过Toll样受体9(TLR9)，用含胞嘧啶-鸟苷的DNA寡核苷酸在Tg2576 AD模型转基因小鼠中刺激了天然免疫系统。与未经治疗的AD小鼠相比，这种治疗方法使皮质(p=0.0001)和血管(p=0.0039)的淀粉样蛋白负荷分别减少了66%和80%。这与Aβ42、Aβ40和Aβ寡聚体水平的显著降低有关。我们还表明，经治疗的转基因小鼠在放射状手臂迷宫中的表现类似于野生型小鼠。我们的数据表明，通过TLR9刺激天然免疫在减少实质和血管淀粉样蛋白负荷方面非常有效，与Aβ寡聚体一起，没有明显的毒性。
The pathogenesis of Alzheimer’s disease (AD) is thought to be related to the accumulation of amyloid β (Aβ) in amyloid deposits and toxic oligomeric species. Immunomodulation is emerging as an effective means of shifting the equilibrium from Aβ accumulation to clearance; however, excessive cell mediated inflammation and cerebral microhemorrhages are two forms of toxicity which can occur with this approach. Vaccination studies have so far mainly targeted the adaptive immune system. In the present study, we have stimulated the innate immune system via the Toll-like receptor 9 (TLR9) with cytosine-guanosine-containing DNA oligodeoxynucleotides in Tg2576 AD model transgenic mice. This treatment produced a 66% and 80% reduction in the cortical (p = 0.0001) and vascular (p = 0.0039) amyloid burden, respectively, compared with nontreated AD mice. This was in association with significant reductions in Aβ42, Aβ40, and Aβ oligomer levels. We also show that treated Tg mice performed similarly to wild-type mice on a radial arm maze. Our data suggest that stimulation of innate immunity via TLR9 is highly effective at reducing the parenchymal and vascular amyloid burden, along with Aβ oligomers, without apparent toxicity.