Hippocampal T2 signal loss and decreased radial arm maze performance in transgenic murine model for AD

Abstract

We propose that Alzheimer’s disease (AD) progression is largely caused by excess reactive oxygen species (ROS) or free radicals created by iron dysregulation. An AD brain is struggling with damage control creating harmful tau tangles and amyloid plaques to deal with the dysregulated iron. We hypothesized that transgenic APP/PS1 (Amyloid precursor protein/ Presenilin-1) and Tau mice would exhibit higher levels of deposits in the brain which can be detected through MRI as well as decreased behavioral performance in radial arm maze tasks. We bred APP/PS1 transgenic mice overexpressing chimeric mouse/human APP-695 with mutations and human PSEN1 carrying the exon-9-deleted variant (PSEN1dE9), and Tau mice overexpressing all six isoforms of hyper-phosphorylated human MAPT (Microtubule associated protein Tau), which were compared with age controlled wild type mice. Mice received a diet of either regular or methionine rich chow as an oxidative stressor. Subgroups received a rescue treatment of either zinc, metformin or clioquinol chow. MRI (Magnetic Resonance Imaging) scans were performed using a Siemens 3 Tesla scanner. Behavioral data was collected using a radial arm maze (RAM) for 2 weeks at each point. Data collection time points were: 1 (baseline), 3, 6 and 9 months. Mean T2 TSE signals from scans on these mice revealed significant signal loss in bilateral hippocampi when compared by age. We also found a significant main effect of genotype and a trend toward significance for genotype and treatment interaction in the mean time mice spent in the RAM. Pairwise comparison showed a significant difference between the time male and female mice spent in the RAM. There was, however, no effect of signal loss or behavior deficit when comparing rescue treatments with or without oxidative insults. The decrease in signal and RAM performance is due to plaque increase and accompanying iron, which offers a possibility to refine the imaging techniques in pursuit of a noninvasive diagnostic biomarker. *Correspondence to: Jonathan J Wisco, PhD, Associate Professor, Boston University School of Medicine, Department of Anatomy and Neurobiology, Laboratory for Translational Anatomy of Degenerative Diseases and Developmental Disorders (TAD4), 72 E Concord St, L-1004, Boston, MA 02118, USA, Tel: 310-746-6647/ Office: 617-358-2002; E-mail: jjwisco@bu.edu