Imaging Core

认知受损的老年人的神经病理通常是多因素的，包括阿尔茨海默病 病理类型、缺血/血管病变、路易小体、海马硬化和TDP-43蛋白病变。 最近，后两者被证明是联系在一起的。TDP-43是积聚在神经元中的主要蛋白质。 泛素化夹杂物(FTLD-U)和肌萎缩侧索硬化症中的夹杂物 硬化症(ALS)，但也在其他与FTLD-U或FTLD-U没有明显关系的疾病中检测到 ALS，为TDP-43的病理机制提供了替代机制。原颗粒蛋白基因突变(GRH) 导致FTLD-U的海马区硬化，几乎所有的突变都是通过减少 原颗粒蛋白表达。从这些观察中不可否认的事实是，即使是部分减少 随着时间的推移，原颗粒会导致严重的神经后果。在细胞培养研究中， 丙粒蛋白可诱导细胞凋亡、caspase介导的TDP-43裂解和TDP-43包涵体。普普通通 GRN 3‘非编码区miRNA结合位点的变异被证明增加FTLD-U的风险 由于前颗粒蛋白表达减少，同样的基因变异容易导致海马体硬化。 这项建议的目的是研究这些现象及其与糖皮质激素的关系。 中介压力。潜在的假设是，由于遗传或其他原因，原颗粒蛋白表达减少 环境因素或两者兼而有之，容易导致神经退化，特别是在海马体。我们 假设原颗粒缺乏易患海马硬化。要解决这个问题 假设，在人类尸检组织和小鼠前颗粒缺乏模型中提出了研究。 在人类中，我们将测定GR/V基因型和脑内原颗粒蛋白水平 没有海马体硬化症。我们假设海马区硬化症将与 导致TDP-43病理的程序性细胞死亡。为此，我们将研究TDP-43的病理学 海马区硬化症与程序性细胞死亡的标志物以及其他可能的应激源 如缺氧、微血管病变和糖皮质激素应激等。动物研究将以 原颗粒基因敲除小鼠和对照组对糖皮质激素介导的应激(身体约束)是否 前颗粒蛋白缺乏的动物的海马区病理更严重。类似的实验将在 与TDP-43转基因小鼠杂交的原颗粒基因敲除小鼠。 相关性(请参阅说明)： 项目4旨在确定原颗粒蛋白基因中常见的遗传变异与风险之间的相互作用 对于应激反应中的海马区病理。这些发现对于理解风险因素具有相关性。 (特别是应激)海马神经元丢失及其遗忘症，这是常见的问题 在老年人身上。

Neuropathology in cognitively impaired elderly individuals is commonly multifactorial, including Alzheimer type pathology, ischemic/vascular lesions, Lewy bodies, hippocampal sclerosis and TDP-43 proteinopathy. Recently, the latter two have shown to be linked. TDP-43 is the major protein that accumulates in neuronal inclusions in frontotemporal degeneration with ubiquitinated inclusions (FTLD-U) and in amyotrophic lateral sclerosis (ALS), but it is also detected in other disorders that show no obvious relationship to FTLD-U or ALS, suggesting alternative mechanisms for TDP-43 pathology. Mutations in the gene for progranulin {GRH) cause FTLD-U with hippocampal sclerosis, and almost all mutations are mediated by decreases in progranulin expression. The undeniable fact from these observations is that even partial decreases in progranulin over time lead to severe neurologic consequences. In cell culture studies, decreases in progranulin induce apoptosis, caspase-mediated TDP-43 cleavage and TDP-43 inclusions. Common variants in miRNA binding sites in the 3'UTR of GRN have been shown to increase the risk of FTLD-U through decreased progranulin expression; the same genetic variants predispose to hippocampal sclerosis. The goals of this proposal are to investigate these phenomena and there relationship to glucocorticoid- mediated stress. The underlying hypothesis is that decreased progranulin expression, due to genetic or environmental factors or both, predisposes to neurodegeneration, particularly in the hippocampus. We hypothesize that deficiencies in progranulin predispose to hippocampal sclerosis. To address this hypothesis, studies are proposed in human autopsy tissue and in a mouse model of progranulin deficiency. In humans we will determine GR/V genotype and levels of progranulin in brains of individuals with and without hippocampal sclerosis. We hypothesize that hippocampal sclerosis will be associated with programed cell death that leads to TDP-43 pathology. To this end we will study TDP-43 pathology in hippocampal sclerosis with respect to markers of programmed cell death, as well as other possible stressors such as hypoxia, microvascular pathology and glucocorticoid stress. The animal studies will subject progranulin knockout mice and controls to glucocorticoid-mediated stress (physical restraint) to see if hippocampal pathology is greater in progranulin deficient animals. Similar experiments will be conducted in progranulin knock-out mice that have been crossbred with TDP-43 transgenic mice. RELEVANCE (See instructions): Project 4 aims to determine the interplay between common genetic variants in the progranulin gene and risk for hippocampal pathology in response to stress. The findings have relevance for understanding risk factors (particularly stress) for hippocampal neuronal loss and its amnestic syndrome, which are common problems in the elderly.