a-Synuclein vulnerability mechanisms and therapeutics in Alzheimer's Disease

项目摘要/摘要 阿尔茨海默病(AD)的特点是多种蛋白质的积聚，包括(APP)/Aβ，Tau， Tdp-43和α-突触核蛋白(α-syn)。然而，这种机制还没有完全被理解。 包括转运所需的内体分选复合体在内的蛋白质聚集清除(ESCRT) 这可能与自噬有关。在前一期资金中，重点是调查 自噬在α-SYN增殖和清除机制中的作用及开发新的免疫疗法 路易体痴呆(DLB)。我们发现α-SYN干扰细胞内转运， 自噬和抗体治疗减少了繁殖和毒性。我们发表了150多篇文章 手稿和我们针对α-SYN的3个项目已经进入I期临床试验。在更新中，我们 研究了α-SYN作为Aβ对AD中特定神经细胞群毒性的中介作用。我们的 假设通过与RABS和ESCRTIII蛋白的相互作用，α-SYN聚集体干扰 神经营养因子(NTF)的神经内体转运导致选择性神经元损伤。 我们的目标：i)研究α-SYN在AD选择性神经元丢失中的作用。 干扰RABS和ESCRTIII导致NTF运输缺陷和II)评估是否有脑穿透 靶向α-SYN的核苷酸可能逆转内体改变并保护选定的网络免受 在公元后退化。我们修订的目标：1)在神经元培养中研究α- SYN通过RABS和ESCRTIII的改变介导AD中选择性神经元易损性；2)确定 条件消融APP小鼠特定神经元群体中α-SYN的体内IF改善 神经退行性变和功能改变；3)评价脑靶向的神经保护作用 APP TG模型中的α-syn siRNA。这些目标与NIA 2012和2015 AD峰会一致 研究建议。更好地理解存在选择性漏洞的潜在机制 AD对于开发针对α-SYN的新疗法至关重要。

Project Summary/Abstract Alzheimer’s disease (AD) is characterized by the accumulation of multiple proteins including (APP)/Aβ, Tau, TDP-43 and alpha-synuclein (α-syn). The mechanisms are not completely understood however alterations in protein aggregate clearance including endosomal sorting complex required for transport (ESCRT) mediated autophagy might be involved. For the previous period of funding, the focus was to investigate the role of autophagy in the mechanisms of propagation and clearance of α -syn and to develop new immunotherapies for the Dementia with Lewy bodies (DLB). We found that α -syn interferes with intracellular trafficking and autophagy and that treatment with antibodies reduced propagation and toxicity. We published over 150 manuscripts and 3 of our programs targeting α -syn have advanced to Phase I clinical trials. In the renewal, we investigated the role of α -syn as a mediator of the toxicity of Aβ to selected neuronal populations in AD. Our HYPOTHESIS is that via interactions with Rabs and ESCRTIII proteins, α -syn aggregates interfere with neuronal endosomal transport of neurotrophic factors (NTFs) leading to selective neuronal damage. Our OBJECTIVES: i) investigate the role of α -syn as mediator of the selective neuronal loss in AD by interfering with Rabs and ESCRTIII leading to defective transport of NTFs and ii) assess if brain-penetrating nucleotides targeting α -syn might reverse the endosomal alterations and protect selected networks from degenerating in AD. Our revised AIMS: 1) Investigate in neuronal cultures the mechanisms through which α - syn mediates selective neuronal vulnerability in AD via alterations in Rabs and ESCRTIII; 2) To determine in vivo if conditional ablation of α -syn in specific neuronal populations in APP mice ameliorates neurodegeneration and functional alterations and 3) To evaluate the neuroprotective effects of brain targeted α -syn siRNA in APP tg models. These goals are in agreement with the NIA 2012 and 2015 AD Summit Research Recommendations. A better understanding of the mechanisms underlying selective vulnerability in AD is crucial for developing novel therapeutics targeting α -syn.