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.
| Serrano, Faridis; Deshazer, Mitchell; Smith, Karen D B et al. (2008) Assessing transneuronal dysfunction utilizing manganese-enhanced MRI (MEMRI). Magn Reson Med 60:169-75 |
| Smith, Karen Dell Brown; Kallhoff, Verena; Zheng, Hui et al. (2007) In vivo axonal transport rates decrease in a mouse model of Alzheimer's disease. Neuroimage 35:1401-8 |
