Cell-Cell Interactions In Alzheimer's disease and related dementias

阿尔茨海默病(以下简称AD)是一种进行性神经退行性疾病，是致命的，没有有效的治疗方法 迄今为止的治愈方法。AD表现为学习记忆认知功能逐渐下降 大脑中的海马体和额叶皮质的选择性萎缩。神经退行性变 与阿尔茨海默病相关的还有淀粉样β42(A？42)斑块的聚集。积累 在AD中，Aβ42斑块和NFT会引发跨大脑区域的进行性神经退化。它不是 明确细胞变化如何有助于从最初的无症状期进入一个阶段 明显的认知能力下降。Aβ42介导的分子遗传学机制 神经退行性变还没有完全被理解。包括模式生物在内的许多策略已经被 精心设计的。果蝇，果蝇，有大量的遗传工具，和相似的基因构成 是研究包括阿尔茨海默病在内的人类疾病的一个极好的模型。果蝇可用于高 全基因组吞吐量--用于治疗性化合物筛选。我们已经培育出一只转基因果蝇 在这个模型中，我们在眼睛的视网膜神经元中错误表达了高水平的人类A？42多肽， 表现为进行性神经元死亡的AD样神经病理。这一稳定的转基因品系展示了 在29℃的温度下，A42介导了近100%的果蝇细胞死亡。我们的目标是利用我们的果蝇眼睛模型 确定(A)下游靶基因和(B)检测AD的报告/传感器，以及(C)寻找复合体 阿尔茨海默病神经病理过程中产生A？42的神经元和野生型神经元之间的相互作用我们 高度保守的生长调控无翼(Wg)/Wnt信号通路是主导的 A？42介导的神经变性的修饰物。第一个目标是确定工作组的参与 Aβ42介导的神经变性中的信号转导。WG信号已被研究在细胞存活和 分化，而不是在神经退化中。我们将测试WG信号通路的调制是否可以 调制Aβ42介导的神经变性。我们将测试WG通路的记者/传感器是否可以 可用于检测A？42介导的神经变性。在第二个目标中，我们将确定Wg途径是否 在野生型细胞或表达Aβ42的细胞中，激活会触发神经退化。我们会用我们的两个 克隆系统以确定野生型神经元和A？42产生之间是否存在串扰 神经元。我们的假设是，异常的Wg信号可能会引发野生型神经元的细胞死亡。这些 建议的研究旨在为研究细胞群体之间的串扰提供一个有用的蓝图 神经退行性疾病。这可能会识别新的生物标记物，这些标记物可能是不同的 在表达Aβ42的神经元和WT神经元之间进行调节。更好地了解CELL的本地环境 进行性神经退行性疾病的死亡是开发新的干预措施减缓的关键下一步 或者阻止疾病的发展。

Alzheimer’s disease (hereafter, AD), a progressive neurodegenerative disorder, is fatal with no effective cure to date. AD manifests as gradual decline in cognitive functions of learning and memory due to selective atrophy of the hippocampus and frontal cerebral cortex in the brain. The neurodegeneration associated with AD also coincides with accumulation of amyloid-beta 42 (Aß42) plaques. The accumulation of Aβ42 plaques and NFTs in AD triggers progressive neurodegeneration across brain regions. It is not clear how cellular changes contribute to the progression from an initial asymptomatic period into a phase of stark cognitive decline. The molecular genetic mechanisms underlying the Aβ42 mediated neurodegeneration are not fully understood. Many strategies including model organisms have been devised. Drosophila melanogaster, fruit fly, with a large array of genetic tools, and similar genetic makeup to humans is an excellent model for human diseases including AD. Drosophila can be used for high throughput genome wide- and for therapeutic compound screens. We have established a transgenic fly model where we misexpress high levels of human Aß42 polypeptides in the retinal neurons of the eye, which exhibits AD like neuropathology of progressive neuronal death. This stable transgenic line exhibits Aß42 mediated cell death in nearly 100% flies at 29oC. Our goal is to employ our Drosophila eye model to identify (a) downstream target genes and (b) reporters/ sensors to detect AD, and (c) look for complex interaction between Aß42-producing and wild-type neurons during Alzheimer’s neuropathology. We identified the highly conserved growth regulatory Wingless (Wg)/Wnt signaling pathway as the dominant modifier of Aß42-mediated neurodegeneration. The first aim is to determine the involvement of Wg signaling in Aβ42-mediated neurodegeneration. Wg signaling has been studied in cell survival and differentiation, and not in neurodegeneration. We will test if modulation of the Wg signaling pathway can modulate Aβ42-mediated neurodegeneration. We will test if the reporters/sensors of the Wg pathway can be used to detect Aß42-mediated neurodegeneration. In the second aim, we will determine if Wg pathway activation triggers neurodegeneration in wild-type cells or in Aβ42-expressing cells. We will use our two clone systems to determine if there is any cross-talk between the wild-type neurons and Aß42 producing neurons. Our hypothesis is that aberrant Wg signaling might trigger cell death in wild-type neurons. These proposed studies aim to provide a useful blueprint to study cross-talk between cell populations in neurodegenerative disease. This may potentially identify new biomarkers that can be differentially regulated between Aβ42-expressing and WT neurons. Better understanding of the local context of cell death in progressive neurodegenerative disease is a vital next step in developing new interventions to slow or halt disease progression.