Roberts Jennifer C, Friel Sarah L, Roman Shilina, Perren Marion, Harper Alex, Davis John B, Richardson Jill C, Virley David, Medhurst Andrew D
Neuroscience Centre of Excellence for Drug Discovery, GlaxoSmithKline, Third Avenue, Harlow, Essex, CM19 5AW, UK.
Exp Neurol. 2009 Apr;216(2):459-70. doi: 10.1016/j.expneurol.2009.01.002.
Chronic inflammation is known to occur in the brains of Alzheimer's Disease (AD) patients, including the presence of activated microglia close to amyloid plaques. We utilised real time autoradiography and immunohistochemistry to investigate microglial activation and the potential anti-inflammatory effects of PPARgamma agonists in the Thy-1 APP695swe/Thy-1 PS-1.M146V (TASTPM) overexpressing transgenic mouse model of AD. An age dependent increase in specific 3H-PK11195 binding to peripheral benzodiazepine receptors (PBR)/translocator protein (18 kDa) (TSPO) was observed in the cortex of TASTPM mice compared to wild type mice, indicative of microglial activation. This was consistent with immunohistochemical data showing age-dependent increases in CD68 immunoreactivity co-localised with amyloid beta (Abeta) deposits. In 10 month old TASTPM mice, pioglitazone (20 mg/kg) and ciglitazone (50 mg/kg) significantly reduced 3H-PK11195 and [3H]DPA-713 binding in cortex and hippocampus, indicative of reduced microglial activation. In AD brain, significant 3H-PK11195 and [3H]DPA-713 binding was observed across all stages of the disease. These results support the use of PBR/TSPO autoradiography in TASTPM mice as a functional readout of microglial activation to assess anti-inflammatory drugs prior to evaluation in AD patients.
已知慢性炎症发生在阿尔茨海默病（AD）患者的大脑中，包括在淀粉样斑块附近存在活化的小胶质细胞。我们利用实时放射自显影和免疫组化技术，在过表达Thy-1 APP695swe/Thy-1 PS-1.M146V（TASTPM）的AD转基因小鼠模型中，研究小胶质细胞的活化以及PPARγ激动剂的潜在抗炎作用。与野生型小鼠相比，在TASTPM小鼠的皮质中观察到特异性3H-PK11195与外周苯二氮䓬受体（PBR）/转位蛋白（18 kDa）（TSPO）结合呈年龄依赖性增加，这表明小胶质细胞被激活。这与免疫组化数据一致，该数据显示与淀粉样β（Aβ）沉积物共定位的CD68免疫反应性呈年龄依赖性增加。在10月龄的TASTPM小鼠中，吡格列酮（20 mg/kg）和环格列酮（50 mg/kg）显著降低了皮质和海马中3H-PK11195和[3H]DPA-713的结合，这表明小胶质细胞活化减少。在AD大脑中，在疾病的所有阶段均观察到显著的3H-PK11195和[3H]DPA-713结合。这些结果支持在TASTPM小鼠中使用PBR/TSPO放射自显影作为小胶质细胞活化的功能读数，以便在对AD患者进行评估之前评估抗炎药物。
