MRI Determination of Axonal Transport Rates in Mouse CNS

描述(申请人提供)：利用我们开发的一种技术--锰增强磁共振成像(MEMRI)轨迹追踪，有可能追踪中枢神经系统(CMS)中的活体神经元通路。锰离子，即Mn2+，是一种钙类似物，可通过钙通道进入神经元。此外，Mn2+通过快速轴突运输沿微管运输，并且也是顺磁性的，使得它可以在自旋晶格(H)加权的MRI图像中被检测到。因此，在疾病进展之前和过程中，可以利用MRI重复测量同一动物体内与Mn2+离子轴突快速运输有关的信号强度的动态变化。 在暴露于过量淀粉样前体蛋白(APR)或淀粉样β蛋白(Aβ)的果蝇和培养的啮齿动物神经元中，已观察到轴突运输缺陷，但运输缺陷的分子基础或运输缺陷与阿尔茨海默病(AD)获得性的时间关系尚不清楚。我们假设：1)随着年龄的增长，正常衰老小鼠的整个大脑的轴突运输速率将会下降；2)在形成神经性斑块之前，过量的APR的存在会导致轴突运输的减少；3)将Mn2+隔离到内质网中的障碍会导致观察到的轴突运输速率的早期下降。 我们计划通过以下特定的目标来验证我们的假设：目的1：我们将测定随着动物年龄的增长，对照组小鼠和APR高表达的AD小鼠模型(TG 2576)中Mn2+离子在CMS中的轴突纵向转运速率；目标2：我们将通过确定随着年龄的增长，正常和TG 2576小鼠中Mn2+摄取和转运的哪些步骤受到影响，来解决这种轴突转运缺陷的机制。

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.