Hippocampal T cell infiltration promotes neuroinflammation and cognitive decline in a mouse model of tauopathy.
Hippocampal T cell infiltration promotes neuroinflammation and cognitive decline in a mouse model of tauopathy.
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DOI：
10.1093/brain/aww270
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发表时间：
2017-01
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影响因子：
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通讯作者：
Blum D
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文献类型：
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作者：
Laurent C;Dorothée G;Hunot S;Martin E;Monnet Y;Duchamp M;Dong Y;Légeron FP;Leboucher A;Burnouf S;Faivre E;Carvalho K;Caillierez R;Zommer N;Demeyer D;Jouy N;Sazdovitch V;Schraen-Maschke S;Delarasse C;Buée L;Blum D
免疫反应在与紧张症相关的认知障碍中的作用尚不清楚。Laurent等人。检测THY-Tau22转基因小鼠海马区CD8+T细胞的分布。T细胞耗竭逆转了这些动物的空间记忆缺陷，支持了海马区T细胞在tau驱动的认知损害中的作用。阿尔茨海默病的特征是淀粉样斑块和tau病理的共同存在，后者与临床症状的进展相关。神经炎性变化被认为是阿尔茨海默病病理生理学的主要因素，尽管它们的确切作用在很大程度上仍存在争议。值得注意的是，免疫反应在多大程度上促进了tau病理所促进的认知损害仍然知之甚少。为了解决这个问题，我们利用了THY-Tau22小鼠模型，该模型逐渐发展出与认知缺陷平行的海马tau病理，并重新评估了tau病理和大脑免疫反应之间的相互关系。除了常规的星形胶质细胞和小胶质细胞反应外，我们在tau转基因小鼠的海马区发现了CD8阳性的T细胞，这与早期的趋化因子反应有关，特别是涉及CCL3。有趣的是，在P301L tau突变的额叶痴呆患者的大脑皮质中也观察到CD8阳性的淋巴细胞浸润。为了深入了解T细胞浸润在THY-Tau22小鼠自发性疾病的病理生理发展中的作用，我们使用抗CD3抗体来慢性去除T细胞。这种抗CD3治疗阻止了tau转基因动物的海马区T细胞的渗透，并在没有tau病理调节的情况下逆转了空间记忆缺陷。总之，这些数据支持了海马区T细胞在tau驱动的病理生理学和阿尔茨海默病和其他tau病的认知障碍中的重要作用。
The role of immune responses in the cognitive impairments associated with tauopathy is unclear. Laurent et al. identify a CD8+ T-cell infiltration in the hippocampus of THY-Tau22 transgenic mice. T-cell depletion reverses spatial memory deficits in these animals, supporting a role for hippocampal T-cell infiltration in tau-driven cognitive impairments. Alzheimer’s disease is characterized by the combined presence of amyloid plaques and tau pathology, the latter being correlated with the progression of clinical symptoms. Neuroinflammatory changes are thought to be major contributors to Alzheimer’s disease pathophysiology, even if their precise role still remains largely debated. Notably, to what extent immune responses contribute to cognitive impairments promoted by tau pathology remains poorly understood. To address this question, we took advantage of the THY-Tau22 mouse model that progressively develops hippocampal tau pathology paralleling cognitive deficits and reappraised the interrelationship between tau pathology and brain immune responses. In addition to conventional astroglial and microglial responses, we identified a CD8-positive T cell infiltration in the hippocampus of tau transgenic mice associated with an early chemokine response, notably involving CCL3. Interestingly, CD8-positive lymphocyte infiltration was also observed in the cortex of patients exhibiting frontemporal dementia with P301L tau mutation. To gain insights into the functional involvement of T cell infiltration in the pathophysiological development of tauopathy in THY-Tau22 mice, we chronically depleted T cells using anti-CD3 antibody. Such anti-CD3 treatment prevented hippocampal T cell infiltration in tau transgenic animals and reverted spatial memory deficits, in absence of tau pathology modulation. Altogether, these data support an instrumental role of hippocampal T cell infiltration in tau-driven pathophysiology and cognitive impairments in Alzheimer’s disease and other tauopathies.