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.

针对小胶质细胞减轻阿尔茨海默氏病病理生物学 概括 阿尔茨海默氏病（AD）是导致年龄相关痴呆的最常见原因导致不可逆的 神经变性和认知能力下降，没有治愈或有效的预防措施。自噬是一个 在所有真核细胞中都发现了细胞反应。广告中的几项研究表明自噬活动是 在神经元细胞中受到损害，并建议这导致淀粉样蛋白β（Aβ）和 神经毒性。很少有报道检查广告大脑中的自噬活动，并建议自噬是 然而，神经元功能障碍，自噬在小胶质细胞（大脑的免疫细胞）中的贡献是 不清楚。我们最近发布的新生成的数据表明，自噬在成年小胶质细胞中受损 来自AD小鼠。更重要的是，我们发现针对几个自噬的特定microRNA（miRNA） 与非AD个体相比，分子在AD患者的大脑中进行了更新 来自AD小鼠模型的大脑和小胶质细胞衍生。 AD中该特定miRNA的表达增加 大脑会导致自噬作用的下调，然后导致降低Aβ的清除率 小胶质细胞。在AIM 1中，我们将确定MIR表达升高的机制。在AIM 2中，我们 将研究减少AD小鼠大脑中的MIR的功能后果和机制 通过它在广告大脑中更新microRNA。我们将确定从中分离出的小胶质细胞的行为 治疗的小鼠。这些实验将使用AD鼠标模型5XFAD和人类样本进行 AD和非AD患者。我们的建议将描述一个新型的药物目标和AD传递方式。