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.

靶向小胶质细胞以减轻阿尔茨海默病的病理生物学 总结 阿尔茨海默病（AD）是导致不可逆性痴呆的年龄相关性痴呆的最常见原因。 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 在所有真核细胞中发现的保守的细胞反应。AD的几项研究表明，自噬活性是 在神经元细胞中受损，并表明这导致淀粉样蛋白-β（Aβ）的清除减少， 神经毒性很少有报道研究AD大脑中的自噬活性，并认为自噬是AD的一个重要机制。 然而，在神经元功能失调的情况下，自噬在小胶质细胞（大脑的免疫细胞）中的作用， 不清楚我们最近发表的新数据显示，自噬在成年小胶质细胞中受损， AD小鼠更重要的是，我们发现了一种特定的microRNA（miRNA），它靶向几种自噬， 与非AD个体相比，AD患者的脑中，以及在 脑和小胶质细胞-来源于AD小鼠模型。这种特异性miRNA在AD中的表达增加 大脑导致自噬效应器下调，从而导致Aβ的清除率降低 小胶质细胞在目标1中，我们将确定miR表达升高的机制。在目标2中， 将研究减少AD小鼠大脑中这种miR的功能后果及其机制 从而使AD脑中的microRNA上调。我们将确定分离的小胶质细胞的行为， 治疗小鼠。这些实验将使用AD小鼠模型5XFAD和人样品进行，来自 AD和非AD患者。我们的建议将描述一种新的药物靶点和AD的给药方式。