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， 治愈至今AD表现为学习和记忆的认知功能逐渐下降， 大脑中海马体和额叶大脑皮层的选择性萎缩。所述神经变性 与AD相关的疾病也与淀粉样蛋白β 42（A β 42）斑块的积累相一致。积累 AD中A β 42斑块和NFT的增加触发了整个脑区的进行性神经变性。不 清楚细胞变化如何促进从最初的无症状期进展到阶段 认知能力明显下降A β 42介导的细胞凋亡的分子遗传学机制 神经退行性变尚未完全了解。包括模式生物在内的许多策略已经被 设计的黑腹果蝇，果蝇，拥有大量的遗传工具，以及相似的遗传组成 是包括AD在内的人类疾病的极好模型。果蝇可用于高 全基因组通量-以及用于治疗性化合物筛选。我们已经建立了一种转基因苍蝇 模型，其中我们在眼睛的视网膜神经元中错误表达高水平的人A β 42多肽， 其表现出进行性神经元死亡的AD样神经病理学。这种稳定的转基因品系表现出 在29 ℃时，A β 42在几乎100%的果蝇中介导细胞死亡。我们的目标是利用果蝇眼睛模型 鉴定（a）下游靶基因和（B）报告基因/传感器以检测AD，和（c）寻找复合物 阿尔茨海默病神经病理学过程中A β 42产生神经元和野生型神经元之间的相互作用。我们 确定了高度保守的生长调节无翅（Wg）/Wnt信号通路为主导 A β 42介导的神经变性的修饰剂。第一个目标是确定工作组的参与情况， A β 42介导的神经变性中的信号传导。已经在细胞存活中研究了WG信号传导， 分化，而不是神经变性。我们将测试Wg信号通路的调节是否可以 调节A β 42介导的神经变性。我们将测试Wg途径的报告基因/传感器是否可以 用于检测A β 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 激活触发野生型细胞或A β 42表达细胞的神经变性。我们会用我们的两个 克隆系统以确定野生型神经元和产生A β 42的神经元之间是否存在任何串扰 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 拟议的研究旨在提供一个有用的蓝图，研究细胞群之间的串扰， 神经退行性疾病这可能会潜在地识别新的生物标志物， 在A β 42表达神经元和WT神经元之间调节。更好地理解细胞的局部环境 进行性神经退行性疾病的死亡是开发新的干预措施以减缓 或阻止疾病发展。

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.