期刊
ALZHEIMERS RESEARCH & THERAPY
卷 11, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s13195-019-0560-6
关键词
Alzheimer's disease; beta-Amyloid; Oligomers; Globulomers; Flavonoid
资金
- National Major Scientific and Technological Special Project for Significant New Drugs Development [2013ZX09103001019]
- Open Research Fund of the State Key Laboratory of Cognitive Neuroscience and Learning
Background Brain amyloid deposition is one of the main pathological characteristics of Alzheimer's disease (AD). Soluble oligomers formed during the process that causes beta-amyloid (A beta) to aggregate into plaques are considered to have major neurotoxicity. Currently, drug development for the treatment of Alzheimer's disease has encountered serious difficulties. Our newly proposed solution is to accelerate the aggregation of A beta to reduce the amount of cytotoxic A beta oligomers in brain tissue. This strategy differs from the existing strategy of reducing the total A beta content and the number of amyloid plaques. Method In this study, we screened a small library and found that a flavonoid compound (ZGM1) promoted the aggregation of beta-amyloid (A beta). We further verified the binding of ZGM1 to A beta 42 using a microscale thermophoresis (MST) assay. Subsequently, we used dot blotting (DB), transmission electron microscopy (TEM), and thioflavin T fluorescence (ThT) measurements to study the aggregation of A beta under the influence of ZGM1. By using cell experiments, we determined whether ZGM1 can inhibit the cytotoxicity of A beta. Finally, we studied the protective effects of ZGM1 on cognitive function in APPswe/PS1 mice via behavioral experiments and measured the number of plaques in the mouse brain by thioflavin staining. Results ZGM1 can bind with A beta directly and mediate a new A beta assembly process to form reticular aggregates and reduce the amount of A beta oligomers. Animal experiments showed that ZGM1 can significantly improve cognitive dysfunction and that A beta plaque deposition in the brain tissue of mice in the drug-administered group was significantly increased. Conclusion Our research suggests that promoting A beta aggregation is a promising treatment method for AD and deserves further investigation.
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