ANALYSIS OF MICROVASCULAR CHANGES IN THE AGING BRAIN

已有数据表明，与年龄相关的和淀粉样蛋白诱导的脑微血管病变是阿尔茨海默病(AD)发病机制的一个潜在促进因素。本项目将研究血管病理、淀粉样蛋白和tau堆积与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前体蛋白(APP)的“瑞典”双突变的小鼠模型中进行研究，以及三组不同的人类尸检标本：1)神经学正常的老年病例，2)轻度认知障碍和早期AD病例，以及3)百岁老人大脑。这些分析将集中在海马体和内嗅觉皮质作为 在大脑老化和阿尔茨海默病中，它们是最早参与退化过程的皮质区域。具体目的I将对三组受试者的海马体和内嗅皮层的血管系统进行详细的定量分析。我们假设血管损伤的程度和退变的反映之间存在强烈的空间和时间关系。我们将使用体视学探头，以区域和层特定的方式对血管密度进行准确的定量评估。SPICAL AIM II将对表达APP“瑞典”突变的Tg2576转基因小鼠的大脑皮层进行可比性分析。我们将测试这样一种假设，即APP(SWE)小鼠表现出与年龄相关的皮质微血管病理，这与在 人体内的广告。此外，我们认为在这些小鼠中淀粉样蛋白的累积沉积导致沉积附近神经元的形态完整性的严重变化。神经元形态将通过计算机重建的海马神经元和新皮质神经元细胞内注射的方式进行定量评估。具体目标III将涉及9.4T(MRM)的体外高分辨率磁共振显微成像。这些MRM数据将与在特定目标II中分析的形态变化有关。我们假设这些转基因小鼠的海马区和内嗅区将出现随年龄增长的体积损失，这将与血管变化的严重程度相关。这 该项目将对与年龄相关的淀粉样蛋白沉积和微血管损伤对对记忆和认知至关重要的脆弱皮质回路中的神经元病理在时间和空间上的相对贡献进行定量评估。

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.