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

项目摘要 该项目旨在设计一种用于治疗突触核蛋白病的创新纳米药物 如帕金森病（PD）、帕金森病痴呆（PDD）或路易痴呆 机构（DLB）。这些与年龄相关的神经退行性疾病的特征在于： 蛋白质α-突触核蛋白（ASYN）的沉积和聚集。慢性和过度ASYN 积累可以引起小胶质细胞的募集，小胶质细胞发挥重要作用， 清除ASYN。小胶质细胞的持续激活损害了正常的降解， ASYN通路，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相关的潜在可行方法。 神经变性核心假设是通过调节ASYN相互作用， 使用小胶质细胞受体，ASYN的细胞内聚集可以被抑制，并且 可以阻止突触核蛋白病的发展 我们的目标是通过设计由以下物质组成的合成纳米颗粒（NPs）来开发纳米治疗剂： 这些分子可以分子靶向特定的小胶质细胞清道夫受体（SR）。 SR介导ASYN的摄取，也催化ASYN寡聚化。在目标1中，我们建议 一种新的NP设计，使得NP可以作为SR的结合配偶体，沿着 ASYN，但是一旦在小胶质细胞内内化，这些纳米颗粒的活性核心区域将 暴露，破坏ASYN的细胞内聚集。在目标2中，我们还将研究 递送抗氧化剂有效载荷以抵消小胶质细胞活化的功效， 改善促炎M1小胶质细胞表型的活化。的影响 纳米粒对小胶质细胞ASYN摄取和细胞内聚集的影响将在体外和体内进行评价。 vivo.除了减少ASYN聚集之外，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表型可以在神经变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持 ASYN的小胶质细胞清除和减少经典活化的 突触核蛋白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.