Donna Jean Cross PhD, Presenter: Research Grant, Hitachi, Ltd Research Grant, Astellas Group

Christopher Allen Potter MD, Abstract Co-Author: Nothing to Disclose

Nathalie M. Martin BA, Abstract Co-Author: Nothing to Disclose

Greg Garwin, Abstract Co-Author: Nothing to Disclose

Rodney Ho PhD, Abstract Co-Author: Nothing to Disclose

Satoshi Minoshima MD, PhD, Abstract Co-Author: License agreement, General Electric Company Research Grant, Koninklijke Philips Electronics NV Research Grant, Hitachi, Ltd Research Consultant, Hamamatsu Photonics KK Grant, Nihon Medi-Physics Co, Ltd Research Grant, Astellas Group Research Grant, Seattle Genetics, Inc

Using MR imaging with manganese (ME-MRI) to assess bulk axonal transport rates in vivo, we reported previously decreased axonal transport in young mice transgenic (Tg) for Alzheimer’s disease (AD). Microtubule stabilizing therapeutics have been shown to improve cognition and decrease pathology in AD Tg mice. For this current study, we hypothesized that intranasal administration of paclitaxel, a microtubule-stabilizing drug would improve transport rates in the olfactory tract of triple transgenic AD mice (3xTg-AD).

Mice, (3xTg-AD, n=15, age=75±10 days) were treated by intranasal lavage with either Paclitaxel (0.6 mg/kg; Hospira, Inc., Lake Forest, IL) or 0.9% saline vehicle in a volume of 5 µl per nostril. Mice received a total of 6 treatments at intervals of 14±0.2 days with post treatment imaging occurring at age=172±16 days. Scanning (14T Bruker MR: T1-weighted MDEFT, TR/TE: 5000ms/1.9ms, resolution 0.140 x 0.140 x 0.25mm3) pre and post treatment occurred at 100 min. and again from 280-350 min after administration of 5 µL of 1M MnCl2 intranasally. After imaging, mice were perfused and brains removed for histopathology. Images were coregistered, normalized and stereotactically aligned to a mouse brain atlas. Volumes of interest in the olfactory nucleus (ON) and lateral olfactory tract (OT) were used to measure average signal intensity change indicating Mn2+ transport. Uptake and rate of transport were estimated.

Lateral olfactory tract axonal transport was decreased 63% between pretreatment time (75 days of age) and post (approximately 6 mo. of age) in 3xTg-AD mice receiving saline treatment. This time period usually includes the onset and development of amyloid-related pathology and initial appearance of fibrillary tau in this Tg model. In comparison, mice receiving intranasal treatment with paclitaxel over the same period of time showed a 65% relative increase in OT transport rates. There were no significant differences in total Mn2+ uptake in the ON between groups, indicating delivery thru activity-dependent Ca2+ channels was not affected by treatment.

The ME-MRI results indicate that microtubule-stabilizing drugs may intervene the AD neuropathological cascade via normalization of axonal transport processes, which are critical to maintain homeostatic neuronal functions.

Microtuble-stabilizing drugs present an exciting new therapeutic option for Alzheimer’s disease.

Cross, D, Potter, C, Martin, N, Garwin, G, Ho, R, Minoshima, S, ME-MRI Demonstrating Improved Axonal Transport after Microtubule Stabilization in Alzheimer Transgenic Mice.  Radiological Society of North America 2014 Scientific Assembly and Annual Meeting, - ,Chicago IL. http://archive.rsna.org/2014/14014448.html