Alzheimer's Disease Research Laboratory, Department of Neurology, Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, 114 16th Street, Charlestown, MA, 02129, USA.
Northeastern University, 360 Huntington Ave, Boston, MA, 02155, USA.
J Neuroinflammation. 2018 Sep 18;15(1):269. doi: 10.1186/s12974-018-1309-z.
Misfolding of microtubule-associated protein tau (MAPT) within neurons into neurofibrillary tangles is an important pathological feature of Alzheimer's disease (AD). Tau pathology correlates with cognitive decline in AD and follows a stereotypical anatomical course; several recent studies indicate that tau pathology spreads inter-neuronally via misfolded tau "seeds." Previous research has focused on neurons as the source of these tau seeds. However, recent studies as well as the data contained herein suggest that microglia, the resident immune cells of the central nervous system, play a direct role in the spread of tau pathology.
Primary adult microglia were isolated from human AD cases and the rTg4510 tauopathy mouse model and used for analysis of gene expression, tau protein by Simoa technology, and quantification of tau seeding using a highly sensitive fluorescence resonance energy transfer (FRET) biosensing cell line for tau seeding and aggregation.
Here, we show that microglia isolated from both human tauopathy and AD cases and the rTg4510 tauopathy mouse model stably contain tau seeds, despite not synthesizing any tau. Microglia releases these tau seeds in vitro into their conditioned media (CM). This suggests that microglia have taken up tau but are incapable of entirely neutralizing its seeding activity. Indeed, when in vitro microglia are given media containing tau seeds, they reduce (but do not eliminate) tau seeding. When microglia are treated with inflammagens such as lipopolysaccharide (LPS), interleukin-1β (IL1β), tumor necrosis factor α (TNFα), or amyloid-β, their ability to reduce tau seeding is unchanged and these factors do not induce seeding activity on their own.
Overall, these data suggest that microglia have a complex role: they are capable of taking up and breaking down seed competent tau, but do so inefficiently and could therefore potentially play a role in the spread of tau pathology.
微管相关蛋白 tau（MAPT）在神经元内错误折叠形成神经纤维缠结，是阿尔茨海默病（AD）的重要病理特征。tau 病理学与 AD 中的认知能力下降相关，且具有典型的解剖学过程；最近的几项研究表明，tau 病理学通过错误折叠的 tau“种子”在神经元间传播。先前的研究集中在神经元作为这些 tau 种子的来源。然而，最近的研究以及本文中的数据表明，小胶质细胞，中枢神经系统的常驻免疫细胞，在 tau 病理学的传播中发挥直接作用。
从小胶质细胞中分离出人类 AD 病例和 rTg4510 tauopathy 小鼠模型中的原代成人小胶质细胞，并用于分析基因表达、Simoa 技术检测 tau 蛋白以及使用高度敏感的荧光共振能量转移（FRET）生物传感器细胞系定量 tau 种子。
在这里，我们表明从小胶质细胞中分离出的人类 tauopathy 和 AD 病例以及 rTg4510 tauopathy 小鼠模型中稳定地含有 tau 种子，尽管它们不合成任何 tau。小胶质细胞在体外将这些 tau 种子释放到它们的条件培养基（CM）中。这表明小胶质细胞已经摄取了 tau，但不能完全中和其种子活性。事实上，当体外小胶质细胞给予含有 tau 种子的培养基时，它们会降低（但不能消除）tau 种子。当小胶质细胞用脂多糖（LPS）、白细胞介素-1β（IL1β）、肿瘤坏死因子 α（TNFα）或淀粉样蛋白-β等炎症因子处理时，它们降低 tau 种子的能力保持不变，这些因子本身不会诱导种子活性。
总的来说，这些数据表明小胶质细胞具有复杂的作用：它们能够摄取和分解具有种子能力的 tau，但效率低下，因此可能在 tau 病理学的传播中发挥作用。
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