Beta-淀粉样蛋白通过多囊泡体调控突触核蛋白聚集的作用机制研究

Beta-淀粉样蛋白（Abeta）病变发生在帕金森病痴呆（PDD）的15-20年之前，而突触核蛋白(alpha-synuclein, Syn)在皮层和海马区的聚集加剧PDD发展,尚没有有效治疗方法，主要为早期预防。因此，深入研究Abeta如何调控Syn的聚集传播显得尤为迫切。本人致力于荧光成像和Syn聚集的研究（Neuron 2019， Acta Neuropathologica 2020），为靶向Abeta的作用通路提供了基础。预实验显示，Abeta抑制多囊泡体向溶酶体转运、融合，抑制Syn预制蛋白纤维（PFF）降解，最终促进Syn聚集。基于此，本项目运用活细胞成像、脑片培养和转基因动物等平台，研究Abeta如何通过影响PFF内吞、溶酶体降解、外泌体释放、基因差异表达来调控Syn聚集，从而避免在体传播。本研究旨在探讨Abeta在PDD病变的靶标，为治疗PDD及相关疾病提供新策略。

Since the aggregation of amyloid-beta appears about 15-20 years ago before the onset of Parkinson’s disease with dementia (PDD), the aggregation of alpha-synuclein in the cortex and hippocampus exacerbates the progression of PDD. Currently, there are no effective compounds to mitigate the disease, most of them are precautionary measures. So, it is most urgent to study the mechanism of how amyloid-beta regulates the aggregation and spreading of alpha-synuclein. Applicant’s research interests are focused on fluorescence live imaging, aggregation of alpha-synuclein inclusions (Neuron 2019, Acta Neuropathologica 2020), these experiences benefit the research of amyloid-beta. In preliminary results, the amyloid-beta inhibited the translocation and fusion of multivesicular bodies with lysosomes, then inhibited the degradation of alpha-synuclein preformed fibrils (PFF), and finally promoted the aggregation of alpha-synuclein. Based on these results, by using live imaging, brain slice cultures, as well as transgenic animal models, we will investigate how amyloid-beta regulates the uptake of PFF, lysosomal degradation, and exosomal release, and answer how these processes contribute to the aggregation of alpha-synuclein, and finally mitigates in vivo spreading. Based on this research, we are trying to identify and optimize new targets of amyloid-beta in PDD progression, and finally providing new strategies to treat PDD and related diseases.