ANALYSIS OF MICROVASCULAR CHANGES IN THE AGING BRAIN

数据显示，年龄相关和淀粉样蛋白诱导的脑微血管病变是阿尔茨海默病（AD）发病机制的潜在因素。该项目将研究血管病理学、淀粉样蛋白和tau蛋白积累以及神经元病理学之间的时空联系。这些假定的相互作用将在表达淀粉样蛋白前体蛋白（APP）的“瑞典”双突变的小鼠模型和三组不同的人类死后标本中进行研究：1）神经学正常的老年病例，2）具有轻度认知障碍和早期AD的病例，和3）百岁老人的大脑。这些分析将重点关注海马体和内嗅皮质， 它们是在脑老化和AD中最早参与退化过程的皮质区域。具体目标我将涉及一个详细的定量分析的血管系统的海马和内嗅皮层在三组人类受试者。我们假设，一个强大的空间和时间的关系将存在于血管损伤的程度和退化的反射。我们将采用体视学探头，以区域和层特异性方式对血管密度进行准确的定量评估。具体目标II将涉及在表达APP“Swedish”突变的Tg2576转基因小鼠的大脑皮层中进行比较分析。我们将检验APP（swe）小鼠显示与年龄相关的皮层微血管病理学的假设， 人类AD此外，我们提出，在这些小鼠中的淀粉样蛋白的累积沉积导致在沉积物附近的神经元的形态完整性的严重变化。将使用海马和新皮质神经元的细胞内注射和计算机重建以定量方式评估神经元形态。特定目标III将涉及9.4 T（MRM）下的离体高分辨率磁共振显微成像。这些MRM数据将与Specific Aim II中分析的形态学改变相关。我们推测，在这些转基因小鼠中，海马和内嗅区的体积将存在年龄依赖性损失，这将与血管变化的严重程度相关。这 该项目将提供一个定量评估，评估与年龄有关的淀粉样蛋白沉积和微血管损伤在时间和空间上对记忆和认知至关重要的脆弱皮层回路中神经元病理学的相对贡献。

Data have emerged implicating age-related and amyloid-induced pathology of the cerebral microvasculature as a potential contributing factor to the pathogenesis of Alzheimer's disease (AD). This project will investigate the spatial and temporal linkage between vascular pathology, amyloid and tau accumulation, and neuronal pathology.These putative interactions will be investigated in a mouse model that expresses the "Swedish" double mutation of the amyloid precursor protein (APP), and three distinct groups of human postmortem specimens: 1) neurologically normal elderly cases, 2) cases with mild cognitive impairment and early AD, and 3) centenarian brains. These analyses will focus on the hippocampus and entorhinal cortex as they are the earliest cortical regions to be involved by the degenerative process during brain aging and in AD. Specific Aim I will involve a detailed quantitative analysis of the vasculature of the hippocampus and entorhinal cortex in the three groups of human subjects. We hypothesize that a strong spatial and temporal relationship will exist between the degree of vascular damage and reflections of degeneration. We will employ stereologic probes to develop an accurate quantitative appraisal of the vasculature density in a region- and layer-specific manner. Specific Aim II will involve a comparable analysis in the cerebral cortex of Tg2576 transgenic mice expressing the "Swedish" mutation of APP. We will test the hypothesis that the APP(swe) mice show an age-related pathology of the cortical microvasculature that is similar to that found in AD in humans. Moreover, we propose that the accrued deposition of amyloid in these mice leads to severe changes in the morphologic integrity of the neurons in the vicinity of the deposits. Neuronal morphology will be assessed in a quantitative manner using intracellular injection of hippocampal and neocortical neurons with computerized reconstruction. Specific Aim III will involve ex vivo high resolution magnetic resonance microimaging at 9.4 T (MRM). These MRM data will be related to the morphologic alterations analyzed in Specific Aim II. We hypothesize that there will be an age-dependent loss of volume in hippocampal and entorhinal regions in these transgenic mice and this will correlate with the severity of vascular changes. This project will provide a quantitative assessment of the relative contribution in time and space of age-related amyloid deposition and microvascular damage to neuronal pathology in vulnerable cortical circuits critical for memory and cognition.