Kv1.3 inhibition as a potential microglia-targeted therapy for Alzheimer's disease: preclinical proof of concept
Kv1.3 inhibition as a potential microglia-targeted therapy for Alzheimer's disease: preclinical proof of concept
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DOI：
10.1093/brain/awx346
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发表时间：
2018-02-01
期刊：
影响因子：
14.5
通讯作者：
Jin, Lee-Way
中科院分区：
文献类型：
--
作者：
Maezawa, Izumi;Nguyen, Hai M.;Jin, Lee-Way
小胶质细胞在阿尔茨海默病的病理生理学中起着重要作用，但临床上还没有有效的小胶质细胞靶向治疗方法。钾离子通道K（v）1.3和K（ir）2.1在调节免疫细胞功能中起重要作用，并且分别在小胶质细胞的“M1样促炎”或“M2样抗炎”状态中被体外研究所牵连。我们在这里发现，淀粉样β寡聚体诱导的表达K（v）1.3和K（ir）2.1在培养的原代小胶质细胞。同样，从阿尔茨海默病模型5xFAD小鼠中急性分离的离体小胶质细胞共表达K（v）1.3和K（ir）2.1以及传统上与M1和M2活化相关的标记物，表明淀粉样蛋白β寡聚体诱导的小胶质细胞活化状态比以前认为的更复杂。使用口服的脑渗透性小分子K（v）1.3阻滞剂PAP-1作为工具，我们发现由淀粉样β寡聚体诱导的促炎和神经毒性小胶质细胞反应需要体外和海马切片中的K（v）1.3活性。由于我们进一步观察到K（v）1.3在转基因阿尔茨海默病小鼠模型和人类阿尔茨海默病大脑的小胶质细胞中高度表达，因此我们假设药理学K（v）1.3抑制可以减轻淀粉样蛋白β聚集体诱导的病理学。事实上，从9月龄开始，用PAP-1的5个月口服方案治疗APP/PS1转基因小鼠，当动物已经表现出认知缺陷和淀粉样蛋白病理学时，减少了神经炎症，降低了大脑淀粉样蛋白负荷，增强了海马神经元可塑性，并改善了行为缺陷。所观察到的脑淀粉样蛋白沉积的减少与PAP-1增强小胶质细胞对淀粉样蛋白-β的摄取的体外发现一致。总的来说，这些结果提供了概念验证数据，以推进K（v）1.3阻滞剂的阿尔茨海默病临床试验。
Microglia significantly contribute to the pathophysiology of Alzheimer's disease but an effective microglia-targeted therapeutic approach is not yet available clinically. The potassium channels K(v)1.3 and K(ir)2.1 play important roles in regulating immune cell functions and have been implicated by in vitro studies in the 'M1-like pro-inflammatory' or 'M2-like anti-inflammatory' state of microglia, respectively. We here found that amyloid-beta oligomer-induced expression of K(v)1.3 and K(ir)2.1 in cultured primary microglia. Likewise, ex vivo microglia acutely isolated from the Alzheimer's model 5xFAD mice co-expressed K(v)1.3 and K(ir)2.1 as well as markers traditionally associated with M1 and M2 activation suggesting that amyloid-beta oligomer induces a microglial activation state that is more complex than previously thought. Using the orally available, brain penetrant small molecule K(v)1.3 blocker PAP-1 as a tool, we showed that pro-inflammatory and neurotoxic microglial responses induced by amyloid-beta oligomer required K(v)1.3 activity in vitro and in hippocampal slices. Since we further observed that K(v)1.3 was highly expressed in microglia of transgenic Alzheimer's mouse models and human Alzheimer's disease brains, we hypothesized that pharmacological K(v)1.3 inhibition could mitigate the pathology induced by amyloid-beta aggregates. Indeed, treating APP/PS1 transgenic mice with a 5-month oral regimen of PAP-1, starting at 9 months of age, when the animals already manifest cognitive deficits and amyloid pathology, reduced neuroinflammation, decreased cerebral amyloid load, enhanced hippocampal neuronal plasticity, and improved behavioural deficits. The observed decrease in cerebral amyloid deposition was consistent with the in vitro finding that PAP-1 enhanced amyloid-beta uptake by microglia. Collectively, these results provide proof-of-concept data to advance K(v)1.3 blockers to Alzheimer's disease clinical trials.