PHARMACOLOGICAL CORRELATES OF AGING AND BRAIN CELL GRAFTS

项目4的目的是从一个特定的神经元的角度探讨与年龄相关的神经退行性变 群体，即蓝斑去甲肾上腺素能（LC-NE）神经元。这些神经元 在正常衰老期间大脑会恶化，但在阿尔茨海默氏症和帕金森氏症的大脑中也会恶化 患者LC-NE神经元的活性可以作为针对损伤的内源性保护， 神经炎症和氧化应激。因此，本项目旨在研究蓝斑在 在衰老过程中维持边缘系统和黑质纹状体系统的整体健康。由于内在 vs.影响神经变性的外在因素在完整的动物中很难描述，我们建议 利用由LC-NE神经元与海马和中脑组合组成的眼内移植物， 黑质多巴胺神经元，以检查这些神经元在衰老和年龄相关的特定功能， 神经变性内在与外在因素也将检查蓝莓饮食（BB）， 与项目1合作，探索其神经保护特性的机制。我们建议 以下两个假设项目4：1）LC-NE神经元在保护其他大脑区域免受 氧化应激和/或炎症，以及这些神经元的年龄相关性变性导致继发性 海马体和中脑黑质区域的损伤2)用蓝莓提取物治疗可以逆转 LC-NE系统的年龄相关性退化，并提高移植物进入老年宿主的存活率。 基于这些假设，我们制定了三个目标，我们将探讨的关系 LC-NE神经支配与年龄相关的炎症和氧化应激标志物之间的关系。项目4将 在蓝莓研究方面与项目1合作，在小胶质细胞标记方面与项目2合作， 项目3在M1/M2特异性标志物方面，以及项目5在蛋白质水平比较方面 随着年龄的增长，神经退行性变的关键标志物的mRNA表达。

Project 4 aims to explore age-related neurodegeneration from the perspective of one particular neuronal population, namely the locus coeruleus noradrenergic (LC-NE) neurons. This neuronal population deteriorates in the brain during normal aging but also in the brain of Alzheimer's and Parkinson's disease patients. The activity of LC-NE neurons may act as an endogenous protection against insults such as neuroinflammation and oxidative stress. Therefore this project aims to study the role of locus coeruleus in maintaining the overall health of the limbic system and the nigrostriatal system during aging. Since intrinsic vs. extrinsic factors influencing neurodegeneration are difficult to delineate in the intact animal, we propose to utilize intraocular transplants consisting of LC-NE neurons in combination with hippocampal and midbrain nigra dopamine neurons, to examine the specific function of these neurons in aging and age-related neurodegeneration. Intrinsic vs. extrinsic factors will also be examined with blueberry diets (BB) in collaboration with Project 1, to explore the mechanism for its neuroprotective properties. We propose the following two hypotheses for Project 4: 1) LC-NE neurons play a role in protecting other brain regions from oxidative stress and/or inflammation, and age-related degeneration of these neurons leads to secondary damage in the hippocampus, and the midbrain nigra region. 2) Treatment with blueberry extract can reverse age-related degeneration of the LC-NE system, and improve graft survival into the aged host. Based on these hypotheses, we have formulated three aims in which we will explore the relationship between LC-NE innervation and age-related inflammatory and oxidative stress markers. Project 4 will collaborate with Project 1 in terms of blueberry studies, with Project 2 in terms of microglial markers, with Project 3 in terms of the M1/M2 specific markers, and with Project 5 in terms of comparison of protein levels with mRNA expression for critical markers of neurodegeneration with aging.