Basheer Neha, Muhammadi Muhammad Khalid, Freites Carlos Leandro, Avila Martin, Momand Miraj Ud Din, Hryntsova Natalia, Smolek Tomas, Katina Stanislav, Zilka Norbert
Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia.
Institute of Histology and Embryology of Mendoza (IHEM), National University of Cuyo, National Scientific and Technical Research Council (CONICET), Mendoza, Argentina.
Front Aging Neurosci. 2024 Oct 21;16:1468602. doi: 10.3389/fnagi.2024.1468602. eCollection 2024.
Alzheimer's disease (AD) is marked by the accumulation of fibrillary aggregates composed of pathological tau protein. Although neuroinflammation is frequently observed in conjunction with tau pathology, current preclinical evidence does not sufficiently establish a direct causal role in tau tangle formation. This study aimed to evaluate whether chronic Toll-like receptor 4 (TLR4) stimulation, induced by a high dose of lipopolysaccharide (LPS, 5 mg/kg), exacerbates neurofibrillary tangle (NFT) pathology in a transgenic mouse model of tauopathy that expresses human truncated 151-391/3R tau, an early feature of sporadic AD.
We utilized a transgenic mouse model of tauopathy subjected to chronic TLR4 stimulation via weekly intraperitoneal injections of LPS over nine consecutive weeks. Neurofibrillary tangle formation, microglial activation, and tau hyperphosphorylation in the brainstem and hippocampus were assessed through immunohistochemistry, immunofluorescence, and detailed morphometric analysis of microglia.
Chronic LPS treatment led to a significant increase in the number of Iba-1 microglia in the LPS-treated group compared to the sham group ( < 0.0001). Notably, there was a 1.5- to 1.7-fold increase in microglia per tangle-bearing neuron in the LPS-treated group. These microglia exhibited a reactive yet exhausted phenotype, characterized by a significant reduction in cell area ( < 0.0001) without significant changes in other morphometric parameters, such as perimeter, circumference, solidity, aspect ratio, or arborization degree. Despite extensive microglial activation, there was no observed reduction in tau hyperphosphorylation or a decrease in tangle formation in the brainstem, where pathology predominantly develops in this model.
These findings suggest that chronic TLR4 stimulation in tau-transgenic mice results in significant microglial activation but does not influence tau tangle formation. This underscores the complexity of the relationship between neuroinflammation and tau pathology, indicating that additional mechanisms may be required for neuroinflammation to directly contribute to tau tangle formation.
阿尔茨海默病（AD）的特征是由病理性tau蛋白组成的纤维状聚集体的积累。尽管神经炎症常与tau病理同时出现，但目前的临床前证据尚不足以充分证实其在tau缠结形成中具有直接因果作用。本研究旨在评估高剂量脂多糖（LPS，5mg/kg）诱导的慢性Toll样受体4（TLR4）刺激是否会加重表达人截短的151-391/3R tau（散发性AD的早期特征）的tau病转基因小鼠模型中的神经原纤维缠结（NFT）病理。
我们利用一个tau病转基因小鼠模型，通过连续九周每周腹腔注射LPS对其进行慢性TLR4刺激。通过免疫组织化学、免疫荧光以及对小胶质细胞的详细形态计量分析，评估脑干和海马中的神经原纤维缠结形成、小胶质细胞活化以及tau过度磷酸化情况。
与假手术组相比，慢性LPS处理导致LPS处理组中Iba-1小胶质细胞数量显著增加（<0.0001）。值得注意的是，LPS处理组中每个带有缠结的神经元的小胶质细胞增加了1.5至1.7倍。这些小胶质细胞表现出反应性但耗竭的表型，其特征是细胞面积显著减小（<0.0001），而其他形态计量参数，如周长、圆周、坚实度、纵横比或分支程度没有显著变化。尽管小胶质细胞广泛活化，但在该模型中主要发生病理变化的脑干中，未观察到tau过度磷酸化的减少或缠结形成的减少。
这些发现表明，tau转基因小鼠中的慢性TLR4刺激会导致显著的小胶质细胞活化，但不影响tau缠结的形成。这突出了神经炎症与tau病理之间关系的复杂性，表明神经炎症直接促成tau缠结形成可能还需要其他机制。
