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）：可以利用我们开发的技术在中枢神经系统（CMS）中痕迹痕量的神经元途径，锰增强的磁共振成像（MEMRI）痕迹跟踪。锰离子MN2+是钙类似物，可以通过钙（Ca2+）通道进入神经元。此外，MN2+通过快速轴突运输沿微管沿微管运输，也是顺磁性的，使其在旋转晶格（H）加权MRI图像中可检测到MRI。因此，可以利用MRI反复测量信号强度的动态变化，这是在疾病进展之前和期间同一动物内MN2+离子快速轴突转运的动态变化。 已经在蝇中观察到轴突运输缺陷，并且培养的啮齿动物神经元暴露于过量的淀粉样蛋白前体蛋白（APR）或淀粉样蛋白β，但尚无运输缺陷的分子基础，也不是运输缺陷的时间关系和阿尔茨海默氏病（AD）的收集时间。我们假设：1）正常老化小鼠随着衰老的衰老而在整个大脑中的轴突运输速率下降2）在形成神经斑块之前，过量APR的存在会导致轴突运输的降低和3）3）3）MN2+隔离到腹膜衰减的早期下降速度中，MN2+将MN2+的隔离率降低。 我们计划通过以下特定目的测试我们的假设：目标1：我们将纵向确定对照小鼠中CMS中MN2+离子的体内轴突运输速率，并将APR过表达AD的APR过表达的AD（TG 2576）为动物年龄； AIM 2：我们将通过确定MN2+摄取中的哪些步骤和转运在正常和TG 2576小鼠中受到影响，从而解决此轴突运输不足的机制。