Therapeutic potential of secreted APPsalpha for Tau associated synaptic dysfunction and pathology

分泌型 APPsalpha 对 Tau 相关突触功能障碍和病理学的治疗潜力

• 批准号: 342000669
• 负责人: Professorin Dr. Ulrike Müller
• 金额: --
• 依托单位: Institut für Pharmazie und Molekulare Biotechnologie (IPMB)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/342000669?language=en
• 关键词: Therapeutic; potential; secreted; APPsalpha; Tau

Alzheimer's disease (AD) is characterized by synaptic dysfunction, dendritic and axonal atrophy, neuronal death and progressive loss of cognitive functions. Two major pathological lesions are hallmark features of AD: neurofibrillary tangles (NFT), composed of aggregated hyperphosphorylated Tau protein and extracellular plaques consisting of Abeta peptides derived from the amyloid precursor protein APP by proteolytical processing. Despite a recent shift towards preventive strategies there is still an urgent need for an effective treatment of patients with clinically established AD. Accumulating evidence indicates that not only the build up of NFTs and Abeta leads to AD, but that loss of physiological APP functions mediated predominantly by the neurotrophic, secreted APPsalpha produced in the alternative non-amyloidogenic pathway contributes to AD pathogenesis. Our previous work indicated a crucial role of APPsalpha for neuroprotection against various forms of cellular stress in vitro and an essential in vivo role of endogenous APPsalpha for synaptic plasticity and cognition. To explore the therapeutic potential of APPsalpha we recently used an AAV based gene therapy approach (to overexpress APPsalpha in the brain of transgenic AD model mice with plaque pathology. Strikingly, we could show that AVV-mediated overexpression of APPsalpha in aged transgenic APP/PS1deltaE9 mice with well established plaque pathology restored synaptic plasticity and rescued spine density deficits. Importantly, AAV-APPsalpha treatment also resulted in a functional rescue of spatial reference memory in the Morris water maze. Here, our goal is to test the more general applicability of APPsalpha treatment for neurodegenerative diseases. In particular, it is unknown whether APPsalpha is also beneficial in mice with Tau pathology, the prominent second hallmark of AD and several other tauopathies. To this end we intend to assess AAV-APPsalpha mediated beneficial effects in a transgenic mouse lines expressing disease associated mutant Tau isoforms. APPsalpha will be expressed either before the onset of Tau pathology (preventive approach) or at later stages with already established pathology (curative approach). This way, we will assess the potential of APPsalpha to ameliorate or rescue Tau induced pathology including effects on synaptic density, synaptic plasticity, neuronal loss and cognitive behavior. Moreover, we intend to delineate the minimal APPsalpha functional domain, which is very important for future therapeutic application. Finally, we intend to get further insight into the molecular mechanisms underlying APPsalpha mediated effects and identify its molecular targets.

阿尔茨海默病(AD)以突触功能障碍、树突和轴突萎缩、神经元死亡和认知功能进行性丧失为特征。两个主要的病理损害是AD的显著特征：神经纤维缠结(NFT)，由聚集的过度磷酸化的Tau蛋白和细胞外斑块组成，细胞外斑块由淀粉样前体蛋白APP经蛋白质分解处理得到的Abeta多肽组成。尽管最近已转向预防战略，但仍迫切需要对临床确诊的阿尔茨海默病患者进行有效治疗。越来越多的证据表明，不仅NFTs和Abeta的积聚导致AD，而且生理性APP功能的丧失主要是由替代的非淀粉样变途径产生的具有神经营养的分泌APPsalpha介导的，参与了AD的发病。我们以前的工作表明，APPsalpha在体外对各种形式的细胞应激具有重要的神经保护作用，而在体内，内源性APPsalpha对突触可塑性和认知具有重要作用。为了探索APPsalpha的治疗潜力，我们最近使用了一种基于AAV的基因治疗方法(在带有斑块病理的转基因AD模型小鼠的大脑中过表达APPsalpha)。值得注意的是，我们可以证明，AVV介导的APPsalpha在老年转基因APP/PS1deltaE9小鼠中的过度表达具有良好的斑块病理，恢复了突触的可塑性，并挽救了脊柱密度缺陷。重要的是，AAV-APPsalpha治疗还导致了Morris水迷宫中空间参考记忆的功能恢复。在这里，我们的目标是测试APPsalpha治疗神经退行性疾病的更广泛的适用性。特别是，目前尚不清楚APPsalpha是否对患有Tau病理的小鼠也有好处，Tau病理是AD和其他几种tauopathy的突出第二个标志。为此，我们打算评估AAV-APPsalpha在表达疾病相关突变Tau亚型的转基因小鼠系中的有益效果。APPsalpha将在Tau病理开始之前表达(预防性方法)或在已建立的病理的后期阶段表达(治疗性方法)。这样，我们将评估APPsalpha改善或挽救Tau诱导的病理改变的潜力，包括对突触密度、突触可塑性、神经元丢失和认知行为的影响。此外，我们打算描绘最小的APPsalpha功能结构域，这对于未来的治疗应用是非常重要的。最后，我们打算进一步深入了解APPsalpha介导的效应的分子机制，并确定其分子靶点。