R-Flurbiprofen Improves Axonal Transport in the Tg2576 Mouse Model of Alzheimer's Disease as Determined by MEMRI

Axonal pathology is a prevalent feature of Alzheimer's disease (AD) and is thought to occur predominantly due to the accumulation of amyloid beta (A beta). However, it remains unclear whether therapeutics geared toward reducing A beta improves axonal deficits. We have previously used Manganese Enhanced MRI to demonstrate that axonal transport deficits occur before plaque formation in the Tg2576 mouse model of Alzheimer's disease. Here we tested whether axonal transport deficits in the Tg2576 mouse model improve in response to the A beta 42 selective lowering agent R-Flurbiprofen (R-F). We demonstrated that in young animals (before A beta plaque formation), R-F treatment reduced A beta 42 levels and coincided with a significant improvement in axonal transport (P = 0.0186). However, in older animals (after plaque formation had occurred), we observed that R-F treatment did not reduce A beta 42 levels although we still observed a significant improvement in axonal transport as assessed with MEMRI (P = 0.0329). We then determined that R-F treatment reduced tau hyper-phosphorylation in the older animals. These data indicate that both A beta 42 and tau comprise a role in axonal transport rate deficits in the Tg2576 model of Alzheimer's Disease. Magn Reson Med 65:1423-1429, 2011. (C) 2010 Wiley-Liss, Inc.