Imaging functional anatomy in the brain of mouse models of human disease

Abstract

Defects in axonal transport have been implicated in a number of neurodegenerative diseases, from the poly-Q diseases like Huntington's disease, to Alzheimer's disease. The temporal sequence by which a pathological process unfolds is often unknown because our detection system relies on fixed tissue. Magnetic resonance imaging (MRI), a non-destructive imaging modality, allows longitudinal studies inside opaque structures in live animals. We use manganese-enhanced MRI (MEMRI) to witness axonal transport within the living brain of animal models of Alzheimer's disease. Mn2+ enters neurons and is transported by endogenous axonal transport. Thus MEMRI allows us for the first time to measure transport dynamics in the living brain. We find that in mice deleted for amyloid precursor protein (APP), a cargo-receptor for transport whose product is the main component of senile plaques, transport of Mn2+ is decreased in the optic nerve and in the important memory circuit from hippocampus to forebrain. Older mice over-expressing mutant APP also display decreased transport, demonstrating a bimodal effect of APP on transport dynamics. Using statistical parametric mapping of genotypic cohorts, sensitive quantitative measurements of transport are possible. Structural MRI also reveals volumetric changes over time. We conclude that MEMRI reveals pathological progression of disease processes in the living brain.