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

项目总结/摘要 阿尔茨海默病（AD）的特征在于多种蛋白质的积累，包括（APP）/Aβ，Tau， TDP-43和α-突触核蛋白（α-syn）。其机制尚未完全了解，但是 包括转运所需的内体分选复合物（ESCRT）介导的蛋白聚集体清除 可能与自噬有关对于前一时期的供资，重点是调查以下方面的作用： 自噬在α -syn增殖和清除机制中的作用，并开发新的免疫疗法， 路易体痴呆症（DLB）我们发现α -syn干扰细胞内运输， 自噬和用抗体处理减少了繁殖和毒性。我们发表了150多篇 我们的3个针对α -syn的项目已进入I期临床试验。在更新中，我们 研究了α -syn作为Aβ对AD中选定神经元群体毒性的介导剂的作用。我们 假设通过与Rabs和ESCRIII蛋白的相互作用，α -syn聚集体干扰了 神经营养因子（NTFs）的神经元内体转运导致选择性神经元损伤。 我们的实验：i）通过以下方法研究α -syn作为AD中选择性神经元丢失的介导剂的作用： 干扰Rabs和ESCRTIII，导致NTFs转运缺陷，和ii）评估脑穿透 靶向α -syn的核苷酸可能逆转内体的改变，并保护选定的网络， 在AD中退化。我们修订的目的：1）在神经元培养中研究α - syn通过Rabs和ESCRTIII的改变介导AD中的选择性神经元脆弱性; 2）为了确定 在APP小鼠的特定神经元群中，如果条件性消融α -syn， 3）评价脑靶向药物的神经保护作用 APP tg模型中的α -syn siRNA。这些目标与NIA 2012年和2015年AD峰会一致 研究建议。更好地理解选择性脆弱性的内在机制， AD对于开发靶向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.