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

阿尔茨海默病和相关痴呆症中的细胞间相互作用

• 批准号: 10711899
• 负责人: Madhuri Kango-Singh
• 金额: $ 31.48万
• 依托单位: UNIVERSITY OF DAYTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711899
• 关键词: Affect; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyloid beta-42; Amyloid beta-Protein; Atrophic; Biological Markers; Brain; Brain region; Cartoons; Caspase; Cell Communication; Cell Death; Cell Differentiation process; Cell Proliferation; Cell Survival; Cells; Cerebral cortex; Complex; Data; Development; Disease; Disease Progression; Drosophila eye; Drosophila genus; Drosophila melanogaster; Etiology; Event; Exhibits; Eye; Gene Expression; Gene Proteins; Genes; Genetic; Goals; Growth; Hippocampus; Human; Impaired cognition; Intervention; Learning; Measures; Mediating; Memory; Mitotic Recombination; Modeling; Molecular; Molecular Genetics; N-terminal; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Pathology; Pathway interactions; Patients; Peptides; Phase; Phosphotransferases; Population; Proteins; Reporter; Role; Sampling; Signal Pathway; Signal Transduction; Study models; System; Testing; Therapeutic; Time; Transgenic Organisms; Translating; WNT Signaling Pathway; Western Blotting; abeta accumulation; antagonist; cell type; cognitive function; early detection biomarkers; experimental study; fly; gain of function; genetic makeup; genome-wide; human disease; human model; loss of function; member; model organism; morphogens; mosaic; neuron loss; neuropathology; neurotoxic; neurotoxicity; new therapeutic target; polypeptide; prevent; progressive neurodegeneration; response; retinal neuron; sensor; tau Proteins; therapeutic target; tool; transcriptome sequencing; transgenic model of alzheimer disease; Affect; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyloid beta-42; Amyloid beta-Protein; Atrophic; Biological Markers; Brain; Brain region; Cartoons; Caspase; Cell Communication; Cell Death; Cell Differentiation process; Cell Proliferation; Cell Survival; Cells; Cerebral cortex; Complex; Data; Development; Disease; Disease Progression; Drosophila eye; Drosophila genus; Drosophila melanogaster; Etiology; Event; Exhibits; Eye; Gene Expression; Gene Proteins; Genes; Genetic; Goals; Growth; Hippocampus; Human; Impaired cognition; Intervention; Learning; Measures; Mediating; Memory; Mitotic Recombination; Modeling; Molecular; Molecular Genetics; N-terminal; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Pathology; Pathway interactions; Patients; Peptides; Phase; Phosphotransferases; Population; Proteins; Reporter; Role; Sampling; Signal Pathway; Signal Transduction; Study models; System; Testing; Therapeutic; Time; Transgenic Organisms; Translating; WNT Signaling Pathway; Western Blotting; abeta accumulation; antagonist; cell type; cognitive function; early detection biomarkers; experimental study; fly; gain of function; genetic makeup; genome-wide; human disease; human model; loss of function; member; model organism; morphogens; mosaic; neuron loss; neuropathology; neurotoxic; neurotoxicity; new therapeutic target; polypeptide; prevent; progressive neurodegeneration; response; retinal neuron; sensor; tau Proteins; therapeutic target; tool; transcriptome sequencing; transgenic model of alzheimer disease

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.

阿尔茨海默氏病（以下称为AD）是一种进行性神经退行性疾病，是致命的，无效 治愈迄今为止。广告表现为学习和记忆的认知功能的年级下降 大脑中海马和额叶皮质的选择性萎缩。神经变性 与AD相关的还与淀粉样蛋白β42（Aß42）斑块的积累相吻合。积累 AD AD的Aβ42斑块和NFT触发了跨大脑区域的进行性神经退行性。它不是 清楚细胞变化如何有助于从初始无症状时期发展到一个阶段 鲜明的认知下降。 Aβ42介导的分子遗传机制 神经变性尚未完全理解。包括模型生物在内的许多策略已经 设计。果蝇黑色素果司机，果蝇，带有大量遗传工具和类似的基因组成 人类是包括AD在内的人类疾病的绝佳模型。果蝇可用于高 吞吐量的基因组广泛和用于治疗化合物筛选。我们已经建立了转基因苍蝇 我们在眼睛残留神经元中高水平的人Aß42多肽的模型， 它表现出诸如进行性神经元死亡的神经病理学之类的广告。这款稳定的转基因线展览品 Aß42在29oC时介导了几乎100％苍蝇的细胞死亡。我们的目标是将我们的果蝇眼模型用于 识别（a）下游靶基因和（b）以检测AD的记者/传感器，以及（c）寻找复杂的 阿尔茨海默氏神经病理学期间，产生Aß42产生和野生型神经元之间的相互作用。我们 确定高度保守的生长调节无翼（WG）/Wnt信号通路为主要 Aß42介导的神经变性的修饰符。第一个目的是确定WG的参与 Aβ42介导的神经变性中的信号传导。 WG信号已研究在细胞存活中， 分化，而不是神经变性。我们将测试WG信号通路的调制是否可以 调节Aβ42介导的神经变性。我们将测试WG途径的记者/传感器是否可以 用于检测Aß42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表达Aβ42的细胞中的神经退行性。我们将使用我们的两个 克隆系统以确定野生型神经元和Aß42之间是否存在串扰 神经元。我们的假设是，异常WG信号传导可能会触发野生型神经元中的细胞死亡。这些 拟议的研究旨在提供有用的蓝图，以研究细胞种群之间的串扰 神经退行性疾病。这可能有可能识别可能是差异化的新生物标志物 在表达Aβ42的神经元之间调节。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制定新的干预措施以减缓的下一步的重要下一步 或停止疾病进展。