Targeting specific MicroRNA to alleviate Alzheimer’s Disease pathobiology

靶向小胶质细胞减轻阿尔茨海默病的病理生物学 摘要 阿尔茨海默病(AD)是导致老年性痴呆的最常见原因，导致不可逆转 神经变性和认知功能下降，没有治愈或有效的预防措施。自噬是一种 在所有真核细胞中都有保守的细胞反应。AD的几项研究表明，自噬活性是 在神经细胞中受到损害，表明这导致淀粉样蛋白-β(Aβ)的清除减少 神经毒性。很少有报告研究了AD大脑中的自噬活动，并认为自噬是 然而，在神经元功能失调的情况下，小胶质细胞(大脑的免疫细胞)的自噬作用是 不清楚。我们最近发表的新数据表明，成人小胶质细胞的自噬功能受到损害。 来自阿尔茨海默病小鼠。更重要的是，我们发现了一种针对几种自噬的特定微RNA(MiRNA) 分子，在AD患者的大脑中上调，与非AD患者相比，以及在 脑和小胶质细胞--源自AD小鼠模型。这一特定miRNA在AD中的表达增加 大脑导致自噬效应器的下调，从而导致Aβ的清除减少 小胶质细胞。在目标1中，我们将确定miR表达上调的机制。在目标2中，我们 将研究减少AD小鼠脑内这种miR的功能后果及其机制 其中microRNA在阿尔茨海默病脑中上调。我们将确定分离的小胶质细胞的行为 治疗过的小鼠。这些实验将使用AD小鼠模型5XFAD和来自 AD患者和非AD患者。我们的提案将描述AD的一种新的药物靶点和给药方式。

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.