Growth arrest of individual senile plaques in a model of Alzheimer's disease observed by in vivo multiphoton microscopy.

ABSTRACT

In Alzheimer's disease, amyloid-beta peptide aggregates in the extracellular space to form senile plaques. The process of plaque deposition and growth has been modeled on the basis of in vitro experiments in ways that lead to divergent predictions either a diffusion-limited growth model in which plaques grow by first-order kinetics, or a dynamic model of continual deposition and asymmetrical clearance in which plaques reach a stable size and stop growing but evolve morphologically over time. The models have not been tested in vivo because plaques are too small (by several orders of magnitude) for conventional imaging modalities. We now report in vivo multiphoton laser scanning imaging of thioflavine S-stained senile plaques in the Tg2576 transgenic mouse model of Alzheimer's disease to test these biophysical models and show that there is no detectable change in plaque size over extended periods of time. Qualitatively, geometric features remain unchanged over time in the vast majority of the 349 plaques imaged and re-imaged. Intervals as long as 5 months were obtained. Nonetheless, rare examples of growth or shrinkage of individual plaques do occur, and new plaques appear between imaging sessions. These results indicate that thioflavine S-positive plaques appear and then are stable, supporting a dynamic feedback model of plaque growth.