Targeting specific MicroRNA to alleviate Alzheimer’s Disease pathobiology

靶向特定 MicroRNA 缓解阿尔茨海默病病理学

• 批准号: 10666871
• 负责人: Amal O Amer
• 金额: $ 67.46万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666871
• 关键词: 3' Untranslated Regions; Abeta clearance; Adult; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyloid beta-Protein; Astrocytes; Autophagocytosis; Behavior; Binding; Brain; Cells; Chronic; Data; Defect; Dementia; Deposition; Deterioration; Down-Regulation; Equilibrium; Eukaryotic Cell; Exposure to; Genetic Transcription; Homeostasis; Human; Hyperactivity; ITGAM gene; Immune; Impaired cognition; Impairment; In Vitro; Individual; Ingestion; Injections; Knowledge; Mannose; Mediating; Memory; Memory Loss; MicroRNAs; Microglia; Modeling; Molecular; Mus; Nerve Degeneration; Neurons; Peptides; Phase; Preventive measure; Process; Production; Proteins; Publishing; Reporting; Role; Sampling; Senile Plaques; Signal Pathway; Sirolimus; Testing; Therapeutic Intervention; Tissues; Transcript; Untranslated RNA; Up-Regulation; Vacuole; abeta accumulation; abeta deposition; age related; brain cell; experimental study; extracellular; human disease; improved; in vivo; inhibition of autophagy; member; mouse model; nanolabel; nanoparticle; neuroprotection; neurotoxicity; new therapeutic target; novel strategies; prevent; receptor; response; sex; tau Proteins; therapeutic evaluation; therapeutic target; transcription factor

Targeting microglia to alleviate Alzheimer’s Disease pathobiology Summary Alzheimer’s disease (AD) is the most common cause of age-related dementia leading to irreversible neurodegeneration and cognitive decline with no cure or effective preventive measures. Autophagy is a conserved, cell response found in all eukaryotic cells. Several studies in AD showed that autophagy activity is compromised in neuronal cells and suggested that this leads to reduced clearance of amyloid-β (Aβ) and neurotoxicity. Few reports examined autophagy activity in the AD brain and suggested that autophagy is dysfunctional in neurons, however, the contribution of autophagy in microglia, the immune cell of the brain, is unclear. Our newly generated data that was recently published show that autophagy is impaired in adult microglia from AD mice. More importantly, we found that a specific microRNA (miRNA), that targets several autophagy molecules, is upregulated in the brain of AD patients when compared to non-AD individuals, as well as in the brain and microglia-derived from an AD mouse model. Increased expression of this specific miRNA in the AD brain leads to down-regulation of autophagy effectors, which is then responsible for reduced clearance of Aβ by microglia. In Aim 1, we will determine the mechanism underlying elevated expression of the miR. In Aim 2, we will investigate the functional consequences of reducing this miR in the brain of AD mouse and the mechanism by which the microRNA is upregulated in AD brain. We will determine the behavior of microglia isolated from treated mice. These experiments will be performed using the AD mouse model 5XFAD and human samples from AD and non-AD patients. Our proposal will characterize a novel drug target and mode of delivery for AD.

靶向小胶质细胞缓解阿尔茨海默病病理学 概括 阿尔茨海默病 (AD) 是导致与年龄相关的痴呆症的最常见原因，导致不可逆转的痴呆症 自噬是一种无法治愈或有效预防措施的神经退行性疾病和认知能力下降。 在所有真核细胞中发现的保守的细胞反应，AD 的多项研究表明自噬活性是存在的。 神经元细胞受到损害，表明这会导致淀粉样蛋白-β (Aβ) 的清除率降低， 很少有报告检查 AD 大脑中的自噬活性并表明自噬是 然而，神经元功能失调，小胶质细胞（大脑的免疫细胞）中自噬的贡献是 我们最近发布的新生成的数据表明，成人小胶质细胞的自噬受到损害。 更重要的是，我们发现了一种针对多种自噬的特定 microRNA (miRNA)。 与非 AD 个体相比，AD 患者的大脑中的分子，以及在 AD 患者的大脑中表达上调。 AD 小鼠模型中的大脑和小胶质细胞中这种特定 miRNA 的表达增加。 大脑导致自噬效应子下调，从而导致 Aβ 清除率降低 在目标 1 中，我们将确定 miR 表达升高的机制。 将研究减少AD小鼠大脑中这种miR的功能后果及其机制 通过这种方式，microRNA 在 AD 大脑中被上调，我们将确定从中分离出的小胶质细胞的行为。 这些实验将使用 AD 小鼠模型 5XFAD 和来自人类的样本进行。 AD 和非 AD 患者的提案将描述 AD 的新药物靶点和给药方式。