SIGNATURE OF REGIONAL AND NEURONAL VULNERABILITY IN AD

AD 中区域和神经元脆弱性的特征

• 批准号: 6098484
• 负责人: BRADLEY T. HYMAN
• 金额: $ 14.43万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6098484
• 关键词: Alzheimer's disease; NMDA receptors; RNA splicing; RNase protection assay; amine oxidoreductase; amyloid proteins; cell cycle proteins; gene expression; histopathology; human tissue; immunocytochemistry; in situ hybridization; mitogen activated protein kinase; neuritic plaques; neuroanatomy; neurofibrillary tangles; nitric oxide synthase; phosphorylation; polymerase chain reaction; postmortem; protein isoforms; tau proteins

Specific cytoarchitectural areas, subfields, and even lamina develop Alzheimer pathological changes, while other are spared. A pattern of hierarchical vulnerability defines areas that are at risk. This proposal will test hypotheses about molecular characteristics that could underlie this pattern of vulnerability. Our previous studies show neurons that develop neurofibrillary tangles (NFT) occur mainly in specific lamina in limbic and association cortices. Senile plaques (SP) are found in a different but consistent hierarchical pattern, with some brain areas substantially more affected than others. We now propose to combine quantitative anatomic analyses of pathological changes, immunohistochemical and in situ hybridization studies, and RNA analyses from microdissected brain regions to examine how neurons that develop NFT differ from those that do not, and how regions that accumulate SP differ from those that are spared. In the first aim, we will pursue preliminary results which that a change occurs in AD in the pattern of tau isoforms expressed. The second and third aims focus on possible tau kinases. Recent studies show that the MAP Kinase (MAPK) family of Pro directed Ser/Thr kinases (ERKs) phosphorylate tau in vitro in a pattern resembling the changes that occur in NFT. We will study ERKs 1 and 2, ERK3 and the p54 MAPKs. We will test the hypothesis that p54 MAPK phosphorylates tau in a PHF tau fashion. Glycogen synthase kinase 3 has also been implicated in tau phosphorylation. These kinases are all highly expressed in brain, but the neuroanatomical regional and cellular distribution of their expression is unknown. We will study the normal patterns of their expression a swell as determine whether or not changes occur in neurons that develop NFT and in the microenvironment surrounding SP. Pilot experiments will be aimed at determining the activation status of these kinases in the AD brain. In AIM 4, we continue our studies of molecules potentially related to SP formation. Our previous studies, in collaboration with Dr. Tanzi (project 4), analyzed expression of APP major splice forms and found no difference between AD and controls. We now turn to the anatomic distribution and expression of a novel isoform of APP, L-APP (lacking exon 15), as well as new members of the APP family, APLP1 and APLP2. We have observed that nitric oxide synthase neurons are spared in AD. In Aim 5, in collaboration with Dr. Young, (project 1), we will determine the phenotype of these spared neurons in terms of tau, kinase, and glutamate receptor expression. In sum, the overall goal of this project will be to advance the profile of vulnerability from anatomical description towards molecular phenotype by generating profiles of tau, the newly described ERK family of protein kinases, and APP family members in vulnerable and spared areas and cells.

特定的细胞结构区域，子场，甚至是薄片 阿尔茨海默氏症病理变化，而其他则幸免。 一个模式 层次脆弱性定义了有风险的区域。 这个建议 将测试有关分子特征的假设 这种脆弱性模式。 我们以前的研究表明神经元 发展神经原纤维缠结（NFT）主要发生在特定的薄片中 边缘和关联皮层。 老年斑块（SP）在一个 不同但一致的分层模式，某些大脑区域 比其他人更有影响。 我们现在建议结合 定量解剖学分析病理变化， 免疫组织化学和原位杂交研究，RNA分析 从微分解的大脑区域来检查如何发展NFT的神经元 与没有不同的区域以及积累SP的区域有所不同 从那些幸免的人那里。 在第一个目标中，我们将追求初步 tau同工型模式中AD中发生变化的结果 表达。 第二和第三的目的集中在可能的tau激酶上。 最近的研究表明，Pro的MAP激酶（MAPK）家族指导 Ser/Thr激酶（ERKS）在类似于模式的体外磷酸化tau NFT中发生的变化。 我们将研究ERK 1和2，ERK3和 P54 MAPK。 我们将测试p54 mapk磷酸化tau的假设 以PHF tau的方式。 糖原合酶激酶3也已经 与tau磷酸化有关。 这些激酶都很高 在大脑中表达，但神经解剖区域和细胞 其表达的分布尚不清楚。 我们将研究正常 他们表达的模式膨胀，因为确定是否改变 发生在发展NFT和周围微环境中的神经元中 sp。 试点实验将旨在确定激活状态 在广告大脑中的这些激酶。 在AIM 4中，我们继续研究 分子可能与SP形成有关。 我们以前的研究 与Tanzi博士的合作（项目4），分析了应用的表达 主要的剪接形式，发现AD和对照之间没有区别。 我们 现在转向新型同工型的解剖分布和表达 App，L-App（缺少外显子15）以及应用的新成员 家庭，APLP1和APLP2。 我们已经观察到一氧化氮合酶 神经元在AD中幸免。 在AIM 5中，与Young博士合作 （项目1），我们将确定这些保留神经元的表型 Tau，激酶和谷氨酸受体表达的术语。 总而言之 该项目的总体目标是提高 从解剖学描述到分子表型的脆弱性 产生新描述的ERK蛋白质家族Tau的曲线 激酶以及易受伤害和宽松区域和细胞的App家族成员。