Lee Sang Hwan, Bae Eun-Jin, Perez-Acuna Dayana, Jung Min Kyo, Han Jong Won, Mook-Jung Inhee, Lee Seung-Jae
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea.
Neuroscience Research Institute, Medical Research Center, Seoul National University, Seoul 03080, Korea.
Brain. 2024 Dec 3;147(12):4105-4120. doi: 10.1093/brain/awae221.
Neuropathological features of Alzheimer's disease include amyloid plaques, neurofibrillary tangles and Lewy bodies, with the former preceding the latter two. However, it is not fully understood how these compound proteinopathies are interconnected. Here, we show that transplantation of amyloid-β oligomer-activated microglia into the striatum of naïve mice was sufficient to generate all the features of Alzheimer's disease, including widespread tauopathy and synucleinopathy, gliosis, neuroinflammation, synapse loss, neuronal death, and cognitive and motor deficits. These pathological features were eliminated by microglia depletion and anti-inflammatory drug administration. Our results suggest the crucial roles of microglia-driven inflammation in development of mixed pathology. This study provides not only mechanistic insights into amyloid-β oligomer-triggered proteinopathies but also a novel animal model recapitulating the salient features of Alzheimer's disease.
阿尔茨海默病的神经病理学特征包括淀粉样斑块、神经原纤维缠结和路易小体，其中前者先于后两者出现。然而，目前尚不完全清楚这些复合性蛋白质病是如何相互关联的。在此，我们表明，将淀粉样β寡聚体激活的小胶质细胞移植到未处理小鼠的纹状体中，足以产生阿尔茨海默病的所有特征，包括广泛的tau蛋白病和α-突触核蛋白病、胶质细胞增生、神经炎症、突触丧失、神经元死亡以及认知和运动缺陷。通过清除小胶质细胞和给予抗炎药物，这些病理特征得以消除。我们的结果表明小胶质细胞驱动的炎症在混合性病理发展中起关键作用。这项研究不仅为淀粉样β寡聚体引发的蛋白质病提供了机制性见解，还提供了一种重现阿尔茨海默病显著特征的新型动物模型。
