| First Author | Park S | Year | 2021 |
| Journal | Sci Rep | Volume | 11 |
| Issue | 1 | Pages | 12043 |
| PubMed ID | 34103615 | Mgi Jnum | J:311273 |
| Mgi Id | MGI:6720116 | Doi | 10.1038/s41598-021-91563-y |
| Citation | Park S, et al. (2021) Quinacrine directly dissociates amyloid plaques in the brain of 5XFAD transgenic mouse model of Alzheimer's disease. Sci Rep 11(1):12043 |
| abstractText | Alzheimer's disease (AD) is the most common type of dementia characterized by the abnormal accumulation of amyloid-beta (Abeta) in the brain. Abeta misfolding is associated with neuroinflammation and synaptic dysfunction, leading to learning and memory deficits. Therefore, Abeta production and aggregation have been one of the most popular drug targets for AD. Failures of drug candidates regulating the aforementioned Abeta cascade stimulated development of immunotherapy agents for clearance of accumulated Abeta in the brain. Here, we report that quinacrine, a blood-brain barrier penetrating antimalarial chemical drug, dissociates Abeta plaques in the brain of AD transgenic mice. When co-incubated with pre-formed Abeta fibrils, quinacrine decreased thioflavin T-positive beta-sheets in vitro, on top of its inhibitory function on the fibril formation. We confirmed that quinacrine induced dissociation of high-molecular-weight Abeta aggregates into low-molecular-weight species by dot blots in association with size cut-off filtrations. Quinacrine was then administered to adult 5XFAD transgenic mice via weekly intravenous injections for 6 weeks, and we found a significant reduction of Abeta plaques and astrocytosis in their cortex and hippocampus. In western blots of quinacrine-administered mouse brains, amelioration of AD-related biomarkers, glial fibrillary acidic protein, postsynaptic protein 95, phosphorylated cAMP response element-binding protein, phosphorylated c-Jun N-terminal kinase were observed. Lastly, quinacrine-stimulated dissociation of misfolded aggregates induced recovery of synaptic function associated with Abeta in excitatory post-synaptic current recordings of primary rat cortical neurons treated with Abeta aggregates and quinacrine. Collectively, quinacrine can directly dissociate Abeta fibrils and alleviate decreased synaptic functions. |
