Microglial-Targeted Nanotherapeutics for Inhibition of Alpha-Synuclein Aggregation and Inflammation in Neurodegenerative Diseases

项目总结 该项目旨在设计一种用于治疗共核病的创新纳米疗法。 例如帕金森氏病(PD)、帕金森病痴呆症(PDD)或路易氏痴呆症 身体(DLB)。这些与年龄相关的神经退行性疾病的特点是 蛋白质α-突触核蛋白(ASYN)的沉积和聚集。慢性和过度的ASYN 蓄积可引起小胶质细胞的募集，而小胶质细胞在 清除ASYN。小胶质细胞的持续激活损害了正常的降解 ASYN的途径，导致内部ASYN聚集和神经炎症的循环。 因此，靶向小胶质细胞是治疗ASYN相关疾病的一种潜在可行的方法 神经退行性变。中心假设是，通过调节ASYN相互作用 有了小胶质细胞受体，ASYN的细胞内聚集可以被抑制，并且 联核症的进展是可以被阻止的。 我们的目标是通过设计由以下组成的合成纳米颗粒(NPs)来开发纳米疗法 可以分子靶向特定小胶质细胞清道夫受体(SRS)的两亲性分子。 SRS不仅参与ASYN的摄取，而且还催化ASYN的齐聚反应。在目标1中，我们建议 一种新的NPs设计，使NPs可以作为SRS的结合伙伴 ASYN，但一旦内化在小胶质细胞内，这些纳米颗粒的活性核心区将 被暴露，扰乱ASYN的细胞内聚集。在目标2中，我们还将调查 运送抗氧化剂有效载荷以对抗小胶质细胞激活的有效性 改善促炎性M1小胶质细胞表型的活化。经济衰退带来的影响 NPS对小胶质细胞摄取ASYN和细胞内聚集的影响将在体外和 活着。除了减少ASYN聚集外，通过以下方式靶向小胶质细胞激活状态 抑制M1小胶质细胞的有害影响或将激活状态切换到 神经保护性M2表型可在神经退行性疾病中提供治疗益处。 这项研究的总体结果将有助于解决维护的关键障碍 ASYN的小胶质细胞清除与减轻经典激活的炎症效应 共核病和其他神经退行性疾病中的小胶质细胞。

PROJECT SUMMARY This project aims to design an innovative nanotherapeutic for treatment of synucleinopathies such as Parkinson's disease (PD), Parkinson's disease dementia (PDD), or dementia with Lewy bodies (DLB). These age-related neurodegenerative diseases are characterized by the deposition and aggregation of the protein alpha-synuclein (ASYN). Chronic and excessive ASYN accumulation can cause the recruitment of microglia cells that play the important role of clearance of ASYN. Sustained activation of microglia compromises the normal degradation pathways of ASYN, leading to a cycle of internal ASYN aggregation and neuroinflammation. Thus targeting microglial cells is a potentially viable approach for treating ASYN related neurodegeneration. The central hypothesis is that that by regulating ASYN interactions with microglial receptors, intracellular aggregation of ASYN can be inhibited, and that the progression of synucleinopathy can be halted. We aim to develop nanotherapeutics by designing synthetic nanoparticles (NPs) composed of amphiphilic molecules that can molecularly target specific microglial scavenger receptors (SRs). SRs mediate the uptake of ASYN and also catalyze ASYN oligomerization. In Aim 1, we propose a novel design for the NPs such that the NPs can serve as binding partners to SRs along with ASYN, but once internalized within microglia, the active core region of these nanoparticles will be exposed, disrupting intracellular aggregation of ASYN. In Aim 2, we will also investigate the efficacy of delivering an antioxidant payload to counteract microglial activation and thus ameliorate the activation of the pro-inflammatory M1 microglial phenotype. The effects of the NPs on microglial ASYN uptake and intracellular aggregation will be evaluated in vitro and in vivo. In addition to decreasing ASYN aggregation, targeting microglial activation states by suppressing the harmful effects of M1 microglia or switching activation states to the neuroprotective M2 phenotype can provide therapeutic benefits in neurodegenerative diseases. The overall outcomes from this study will help to address the critical barriers of maintaining microglial clearance of ASYN and decreasing the inflammatory effects of classically activated microglia within synucleinopathies and other neurodegenerative diseases.