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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos 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

项目摘要

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（以下简称AD）是一种致命的神经退行性疾病，是致命的，无效治愈迄今为止。在大脑中的海马和额叶皮层的选择性萎缩与AD相关的是淀粉样蛋白β42（Aß42）斑块的积累 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。清楚细胞变化如何促进从初始无症状时期的发展 Aβ42介导的分子遗传机制的鲜明认知下降神经变性尚未完全了解包括模型生物在内的许多策略设计。人类是包括AD在内的人类疾病的绝佳模型。投掷基因组宽，用于治疗化合物。我们在眼睛的视网膜神经元中高水平的人Aß42多肽的模型，表现出类似于进度神经元死亡的神经病理。 Aß42介导的细胞死亡在29oC时近100％苍蝇。识别（a）下游靶基因和（b）以检测AD的记者/传感器，以及（c）寻找复杂的在阿尔茨海默氏神经病理学期间，Aß42产生和野生型神经元之间的相互作用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。 Aβ42介导的神经变性中的信号传导。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。用于检测Aß42介导的神经变性。激活触发野生型细胞或表达Aβ42的细胞中的神经退行性。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支撑研究旨在提供有用的蓝图，以研究细胞受欢迎程度之间的串扰神经退行性疾病。在表达Aβ42和WT神经元之间定期。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计划。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

N-Acetyltransferase 9 ameliorates Aβ42-mediated neurodegeneration in the Drosophila eye.

DOI：
10.1038/s41419-023-05973-z
发表时间：
2023-07-28
期刊：
CELL DEATH & DISEASE
影响因子：
9
作者：
Deshpande, Prajakta;Chimata, Anuradha Venkatakrishnan;Snider, Emily;Singh, Aditi;Kango-Singh, Madhuri;Singh, Amit
通讯作者：
Singh, Amit

miR-277 targets the proapoptotic gene-hid to ameliorate Aβ42-mediated neurodegeneration in Alzheimer's model.

DOI：
10.1038/s41419-023-06361-3
发表时间：
2024-01-18
期刊：
CELL DEATH & DISEASE
影响因子：
9
作者：
Deshpande, Prajakta;Chen, Chao-Yi;Chimata, Anuradha Venkatakrishnan;Li, Jian-Chiuan;Sarkar, Ankita;Yeates, Catherine;Chen, Chun-Hong;Kango-Singh, Madhuri;Singh, Amit
通讯作者：
Singh, Amit

Editorial: Protein misfolding, altered mechanisms and neurodegeneration.