MRI Determination of Axonal Transport Rates in Mouse CNS

小鼠中枢神经系统轴突运输速率的 MRI 测定

• 批准号: 6895388
• 负责人: ROBIA G PAUTLER
• 金额: $ 13.88万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6895388
• 关键词: Alzheimer' s disease; aging; amyloid proteins; bioimaging /biomedical imaging; brain imaging /visualization /scanning; calcium flux; colorimetry; electron microscopy; endoplasmic reticulum; fluorescence microscopy; fluorescent dye /probe; genetically modified animals; hippocampus; laboratory mouse; longitudinal animal study; magnetic resonance imaging; manganese; neuritic plaques; neuronal transport; neuropathology; olfactory lobe; optic nerve; substantia nigra

DESCRIPTION (provided by applicant): It is possible to tract trace neuronal pathways in vivo in the central nervous system (CMS) utilizing a technique that we developed, Manganese Enhanced Magnetic Resonance Imaging (MEMRI) tract tracing. Manganese ion, Mn2+, is a calcium analogue and can enter neurons through calcium (Ca2+) channels. Furthermore, Mn2+ is transported along microtubules via fast axonal transport and is also paramagnetic, rendering it MRI detectable in spin-lattice (H)-weighted MRI images. It is therefore possible to utilize MRI to repeatedly measure dynamic changes in signal intensity, relfective of fast axonal transport of Mn2+ ion, within the same animal before and during disease progression. Axonal transport deficits have been observed in flies and cultured rodent neurons exposed to excess amyloid precursor protein (APR) or amyloid-beta, but neither the molecular basis of the transport deficit nor the temporal relationship of the transport deficit and the acquisition of Alzheimer's Disease (AD) are known. We hypothesize that: 1) Normal aging mice will exhibit declines in axonal transport rates throughout the brain as aging ensues 2) The presence of excess APR causes a reduction in axonal transport prior to the formation of neuritic plaques and 3) Impairment in the sequestering of Mn2+ into the endoplasmic reticulum results in the observed early decline in axonal transport rates. We plan to test our hypotheses through the following Specific Aims: Aim 1: We will determine longitudinally the in vivo axonal transport rates of Mn2+ ion in the CMS in control mice and an APR overexpressing mouse model of AD (TG 2576) as the animals age; Aim 2: We will resolve the mechanism of this axonal transport deficit by determining which steps in Mn2+ uptake and transport are affected in normal and TG 2576 mice as aging ensues.

描述（由申请人提供）：利用我们开发的锰增强磁共振成像（MEMRI）束追踪技术，可以在中枢神经系统（CMS）中体内追踪神经元通路。锰离子，Mn 2+，是钙类似物，可以通过钙（Ca 2+）通道进入神经元。此外，Mn 2+通过快速轴突运输沿着微管运输，并且也是顺磁性的，使其在自旋晶格（H）加权MRI图像中可以被MRI检测到。因此，有可能利用MRI重复测量信号强度的动态变化，反映了Mn 2+离子的快速轴突运输，在同一动物疾病进展之前和期间。 在暴露于过量淀粉样前体蛋白（APR）或淀粉样β蛋白的果蝇和培养的啮齿类动物神经元中观察到轴突运输缺陷，但运输缺陷的分子基础和运输缺陷与阿尔茨海默病（AD）的时间关系均未知。我们假设：1）正常衰老小鼠将表现出整个脑的轴突运输速率随着衰老而下降2）过量APR的存在导致在神经炎斑块形成之前轴突运输的减少和3）Mn 2+螯合到内质网中的损害导致观察到的轴突运输速率的早期下降。 我们计划通过以下具体目的来测试我们的假设：目的1：我们将纵向确定对照小鼠和APR过表达AD小鼠模型（TG 2576）中CMS中Mn 2+离子的体内轴突转运速率;目的2：我们将通过确定Mn 2+在轴突运输中的哪些步骤来解决这种轴突运输缺陷的机制。正常小鼠和TG 2576小鼠的摄取和转运随着衰老而受到影响。