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

阿尔茨海默病（Alzheimer's disease，AD）是一种以突触功能障碍、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的疾病。两种主要的病理学病变是AD的标志性特征：神经元缠结（NFT），其由聚集的过度磷酸化的Tau蛋白组成;和细胞外斑块，其由通过蛋白水解加工从淀粉样前体蛋白APP衍生的Abeta肽组成。尽管最近转向预防策略，但仍迫切需要有效治疗临床确诊的AD患者。越来越多的证据表明，不仅NFT和Abeta的积累导致AD，而且主要由在替代的非淀粉样蛋白生成途径中产生的神经营养分泌型APP α介导的生理APP功能的丧失有助于AD发病机制。我们以前的工作表明，APPsalpha对各种形式的细胞应激的神经保护在体外和内源性APPsalpha的突触可塑性和认知在体内的重要作用的关键作用。为了探索APP α的治疗潜力，我们最近使用了基于AAV的基因治疗方法（在具有斑块病理学的转基因AD模型小鼠的脑中过表达APP α）。引人注目的是，我们可以表明，AVV介导的过表达的APP/PS1 deltaE 9老年转基因小鼠与斑块病理恢复突触可塑性和救援的棘密度赤字。重要的是，AAV-APP α处理还导致Morris水迷宫中空间参考记忆的功能性拯救。在这里，我们的目标是测试APPsalpha治疗神经退行性疾病的更普遍的适用性。特别地，不知道APPalpha是否在具有Tau病理学的小鼠中也是有益的，Tau病理学是AD和几种其他Tau病理学的突出的第二标志。为此，我们打算评估AAV-APP α在表达疾病相关突变体Tau同种型的转基因小鼠系中介导的有益作用。APP α将在Tau病理学发作之前（预防性方法）或在已经建立的病理学的后期阶段（治疗性方法）表达。这样，我们将评估APP α改善或挽救Tau诱导的病理学的潜力，包括对突触密度、突触可塑性、神经元损失和认知行为的影响。此外，我们打算描绘最小的APPsalpha功能域，这是非常重要的，为未来的治疗应用。最后，我们打算进一步深入了解APPsalpha介导的作用的分子机制，并确定其分子靶点。

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.