Associations of amyloid-β oligomers and plaques with neuropathology in the App NL-G-F mouse

作者：Jiabin Tang, Helen Huang, Robert C. J. Muirhead, Yue Zhou, Junheng Li, John DeFelice, Maksym V. Kopanitsa, Lutgarde Serneels, Karen Davey, Bension S. Tilley, Steve Gentleman, Paul M. Matthews · 发表于：Brain Communications · 年份：2024 · DOI：10.1093/braincomms/fcae218 · 被引用次数：11 · 研究领域：Alzheimer's disease research and treatments、Neuroinflammation and Neurodegeneration Mechanisms、S100 Proteins and Annexins

Abstract Amyloid-β pathology and neurofibrillary tangles lead to glial activation and neurodegeneration in Alzheimer’s disease. In this study, we investigated the relationships between the levels of amyloid-β oligomers, amyloid-β plaques, glial activation and markers related to neurodegeneration in the AppNL-G-F triple mutation mouse line and in a knock-in line homozygous for the common human amyloid precursor protein (Apphu mouse). The relationships between neuropathological features were characterized with immunohistochemistry and imaging mass cytometry. Markers assessing human amyloid-β proteins, microglial and astrocytic activation and neuronal and synaptic densities were used in mice between 2.5 and 12 months of age. We found that amyloid-β oligomers were abundant in the brains of Apphu mice in the absence of classical amyloid-β plaques. These brains showed morphological changes consistent with astrocyte activation but no evidence of microglial activation or synaptic or neuronal pathology. In contrast, both high levels of amyloid-β oligomers and numerous plaques accumulated in AppNL-G-F mice in association with substantial astrocytic and microglial activation. The increase in amyloid-β oligomers over time was more strongly correlated with astrocytic than with microglia activation. Spatial analyses suggested that activated microglia were more closely associated with amyloid-β oligomers than with amyloid-β plaques in AppNL-G-F mice, which also showed age-dependent decrease...