BIOMARKERS BRAIN PATHOLOGY: RISKS FOR ALZHEIMER?S DISEASE AND DRUG ADDICTION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 A蛋白质是阿尔茨海默病早期发展的一个重要因素，阿尔茨海默病是一种老年痴呆症，往往影响女性多于男性。在阿尔茨海默氏病中，A？聚集成称为老年斑的异常结构，以及称为寡聚体的较小的有毒组件。我们假设，大脑中的A？含量可能会因更年期伴随的激素变化而增加。在这项研究中，我们正在研究一种经过基因工程改造的小鼠模型，以产生人类A？。我们使用了一种叫做VCD的化学物质，它选择性地消耗卵巢中的某些细胞，以创造一种类似更年期的激素状态。 我们最近完成了我们的子项目的第一个体内阶段，其中治疗的小鼠在VCD给药后的几个月内缓慢停止循环。对第一组小鼠大脑的初步免疫组织化学分析表明，实验组和对照组小鼠的大脑中都有老年斑，并且绝经期小鼠和正常小鼠的老年斑数量相似。研究的第二阶段正在进行中，我们正在研究卵巢被切除的小鼠。当第二阶段完成时，我们将使用MALDI-TOF分析所有大脑中的A？。 与此同时，我们正在研究一种通过MALDI-TOF分析合成A？的方案。我们期望通过MALDI-TOF对A <$进行深入分析将证明A <$蛋白亚型的差异。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The A¿ protein is an important factor in the early development of Alzheimer's disease, a dementing disorder of old age that tends to affect women more than men. In Alzheimer's disease, A¿ aggregates into abnormal structures called senile plaques, as well as smaller, toxic assemblies called oligomers. We hypothesize that the amount of A¿ in the brain may be increased by the hormonal changes that accompany menopause. In this study, we are studying a mouse model that has been genetically engineered to produce human A¿. We have used a chemical called VCD, which selectively depletes certain cells in the ovary, to create a hormonal state that resembles menopause. We recently completed the first in vivo phase of our subproject, in which treated mice slowly stopped cycling over a period of several months following VCD administration. Preliminary immunohistochemical analysis of brains from the first group of mice indicate that both experimental and control mice have senile plaques in the brain, and that the number of senile plaques is similar in menopausal and normal mice. A second phase of the study is ongoing, in which we are studying mice that have had their ovaries removed. When the second phase is completed, we will analyze all brains for A¿ using MALDI-TOF. Meanwhile, we are working on a protocol for analyzing synthetic A¿ by MALDI-TOF. We expect that in-depth analysis of A¿ by MALDI-TOF will demonstrate differences in subtypes of the A¿ protein.