Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, neuritic plaque deposition and pre-fibrillar oligomers in 5XFAD mouse model of Alzheimer's disease.
Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, neuritic plaque deposition and pre-fibrillar oligomers in 5XFAD mouse model of Alzheimer's disease.
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DOI：
10.1186/s13024-018-0244-x
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发表时间：
2018-03-01
影响因子：
15.1
通讯作者：
Glabe CG
中科院分区：
文献类型：
--
作者：
Sosna J;Philipp S;Albay R 3rd;Reyes-Ruiz JM;Baglietto-Vargas D;LaFerla FM;Glabe CG
除了淀粉样β蛋白聚集和含有tau的神经纤维缠结沉积这两个主要的经典特征外，神经炎症在阿尔茨海默病(AD)的病理生理学中扮演着一个重要但尚不清楚的角色。小胶质细胞被认为是AD期间神经炎症的关键介质，并通过平衡神经毒性和神经保护事件来调节脑内稳态。我们之前已经报道过有证据表明，神经性斑块是由神经元内积累的淀粉样蛋白并进一步招募Iba1阳性细胞的死亡神经元衍生而来的，Iba1阳性细胞在神经元死亡或神经性斑块成熟或两者兼而有之中发挥作用。为了研究小胶质细胞对神经炎斑块形成的影响，我们用选择性集落刺激因子1受体(CSF1R)抑制剂PLX3397治疗两个月大的5XFAD小鼠，为期3个月，结果显示小胶质细胞显著消融。治疗结束后，我们立即分析了神经元内淀粉样蛋白和神经元斑的数量，并进行了行为研究，包括Y迷宫、恐惧条件反射和高架+迷宫。我们发现，早期长期服用PLX3397可以显著减少神经元内淀粉样蛋白和神经性斑块的沉积。PLX3397治疗的年轻5XFAD小鼠还显示出脑裂解物中可溶纤维淀粉样寡聚体的显著减少，血浆中可溶纤维前低聚物的耗尽，以及通过恐惧条件反射测试衡量的认知功能的改善。我们的研究结果表明，CSF1R信号，无论是直接作用于神经元还是由小胶质细胞介导，对于神经元内淀粉样蛋白的积聚和神经性斑块的形成都是至关重要的，这表明这两个事件在导致神经退行性变和神经性斑块形成的因果路径中串联在一起。CSF1R抑制剂是潜在的预防或治疗方法，针对神经元内淀粉样蛋白和神经性斑块形成的最早阶段。
Besides the two main classical features of amyloid beta aggregation and tau-containing neurofibrillary tangle deposition, neuroinflammation plays an important yet unclear role in the pathophysiology of Alzheimer’s disease (AD). Microglia are believed to be key mediators of neuroinflammation during AD and responsible for the regulation of brain homeostasis by balancing neurotoxicity and neuroprotective events. We have previously reported evidence that neuritic plaques are derived from dead neurons that have accumulated intraneuronal amyloid and further recruit Iba1-positive cells, which play a role in either neuronal demise or neuritic plaque maturation or both. To study the impact of microglia on neuritic plaque development, we treated two-month-old 5XFAD mice with a selective colony stimulation factor 1 receptor (CSF1R) inhibitor, PLX3397, for a period of 3 months, resulting in a significant ablation of microglia. Directly after this treatment, we analyzed the amount of intraneuronal amyloid and neuritic plaques and performed behavioral studies including Y-maze, fear conditioning and elevated plus maze. We found that early long-term PLX3397 administration results in a dramatic reduction of both intraneuronal amyloid as well as neuritic plaque deposition. PLX3397 treated young 5XFAD mice also displayed a significant decrease of soluble fibrillar amyloid oligomers in brain lysates, a depletion of soluble pre-fibrillar oligomers in plasma and an improvement in cognitive function measured by fear conditioning tests. Our findings demonstrate that CSF1R signaling, either directly on neurons or mediated by microglia, is crucial for the accumulation of intraneuronal amyloid and formation of neuritic plaques, suggesting that these two events are serially linked in a causal pathway leading to neurodegeneration and neuritic plaque formation. CSF1R inhibitors represent potential preventative or therapeutic approach that target the very earliest stages of the formation of intraneuronal amyloid and neuritic plaques.
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影响因子：
4.9
作者：
Garcia S;Hartkamp LM;Malvar-Fernandez B;van Es IE;Lin H;Wong J;Long L;Zanghi JA;Rankin AL;Masteller EL;Wong BR;Radstake TR;Tak PP;Reedquist KA
通讯作者：
Reedquist KA
影响因子：
15.1
作者：
Kayed R;Head E;Sarsoza F;Saing T;Cotman CW;Necula M;Margol L;Wu J;Breydo L;Thompson JL;Rasool S;Gurlo T;Butler P;Glabe CG
通讯作者：
Glabe CG
影响因子：
15.1
作者：
Kayed R;Canto I;Breydo L;Rasool S;Lukacsovich T;Wu J;Albay R 3rd;Pensalfini A;Yeung S;Head E;Marsh JL;Glabe C
通讯作者：
Glabe C
DOI：
10.1073/pnas.0904532106
发表时间：
2010-02-02
影响因子：
11.1
作者：
Friedrich, Ralf P.;Tepper, Katharina;Faendrich, Marcus
通讯作者：
Faendrich, Marcus
影响因子：
2.3
作者：
Poulin, Stephane P.;Dautoff, Rebecca;Morris, John C.;Barrett, Lisa Feldman;Dickerson, Bradford C.
通讯作者：
Dickerson, Bradford C.