SELECTIVE NEURONAL PATHOLOGY IN THE DEVELOPMENT OF DEMENTIA

许多证据表明tau蛋白和淀粉样蛋白相关的细胞改变是阿尔茨海默病（AD）发病机制的主要影响因素。虽然已经在人脑中进行了大量的神经元病理学研究，但是很少以评估病理损伤的进展对所鉴定的神经元亚群的形态完整性的影响的方式进行，并且通常不是定量的。本项目将研究异常磷酸化tau蛋白和淀粉样蛋白积累之间的时空联系，以及神经化学和形态学特征的新皮质锥体细胞不同亚型中树突萎缩和棘缺失。等 将在四组人死后样本中研究推定的相互作用：1）神经学正常的老年病例，2）轻度认知障碍和早期AD病例，3）中度痴呆病例，和4）重度AD病例，以及仅表达人tau基因的小鼠模型。早期AD病例将成为一组特别有趣的大脑，因为它们将使我们能够确定新皮层神经元中树突功能的最早变化，这些神经元具有增强对AD退行性过程的脆弱性的已知风险。基于我们实验室的体视学分析，我们预期一小群富含非磷酸化神经丝的大的新皮层神经元， 第一个包含树突状病变的阶段之前，神经元缠结（NFT）正在形成和痴呆变得明显。这些分析将集中在前额叶皮层的布罗德曼9区。第9区是AD中一个严重和早期受影响的新皮层区域，我们已经广泛地描述了其选择性神经元脆弱性。在这个项目中，我们将通过分析细胞改变及其与淀粉样蛋白沉积和年龄相关神经元病理学的关系，在单个神经元形态学水平上，扩展在前一个资助期间收集的已识别神经元亚组的区域体视学评估。在小鼠中的分析将使我们能够跟踪活体动物的动态变化，在对这些标本进行详细的形态学切片之前获得非常高分辨率的成像数据集， 分析，并提供了神经元的定量分析，潜在的退化风险，具有更高的分辨率水平比将在人类死后材料中实现。总之，该项目将提供一个定量评估，在AD的情况下，不同的严重程度，年龄相关的神经炎病理，淀粉样蛋白加工的早期阶段，老年斑的相对贡献，选择性脆弱的神经元亚群subserving皮层电路的记忆和认知的关键逐步消亡。

Much evidence points to tau- and amyloid-related cellular alterations as major contributing factors to the pathogenesis of Alzheimer's disease (AD). Although numerous studies of neuronal pathology have been carried out in the human brain, they have rarely been performed in a way to assess the effects of the progression of pathological lesions on the morphologic integrity of identified neuronal subpopulations and have generally not been quantitative. This project will investigate the spatial and temporal linkage between abnormally phosphorylated tau and amyloid accumulation, and dendritic atrophy and spine loss in different subtypes of neocortical pyramidal cells characterized by neurochemical and morphologic features. Such putative interactions will be investigated in four groups of human postmortem specimens: 1) neurologically normal elderly cases, 2) cases with mild cognitive impairment and early AD, 3) cases with moderate dementia, and 4) severe AD cases, as well as in a mouse model that expresses only the human tau gene. The early AD cases will emerge as a particularly interesting group of brains as they will permit us to pinpoint the earliest changes in dendritic function in neocortical neurons that have a known risk of enhanced vulnerability to the degenerative process of AD. Based on stereologic analyses from our laboratory, we expect that a small subgroup of large neocortical neurons enriched in nonphosphorylated neurofilaments are the first to contain dendritic lesions that precede the stage at which neurofibrillary tangles (NFT) are forming and dementia becomes evident. These analyses will focus on Brodmann's area 9 in the prefrontal cortex. Area 9 is a severely and early affected neocortical field in AD, which we have extensively characterized in terms of selective neuronal vulnerability. In this project we will expand the regional stereologic assessments of identified neuronal subgroups gathered during the previous funding period by analyzing cellular alterations and their relationships to deposition of amyloid and age-related neuronal pathology at the level of individual neuron morphology. The analyses in mice will permit us to follow the dynamic changes in live animals, obtain very high resolution imaging datasets prior to sectioning these specimens for detailed morphologic analyses, and provide quantitative analyses of neurons potentially at risk of degeneration with a much higher level of resolution than would be achievable in human postmortem materials. Altogether this project will provide a quantitative assessment, in AD cases of different severity, of the relative contribution of age-related neuritic pathology, early stages of amyloid processing, and senile plaques, to the progressive demise of selectively vulnerable neuronal subsets subserving cortical circuits critical for memory and cognition.