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

In Alzheimer's disease, amyloid-beta peptide aggregates in the extracellula r 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 pl aques grow by first-order kinetics, or a dynamic model of continual deposit ion and asymmetrical clearance in which plaques reach a stable size and sto p growing but evolve morphologically over time. The models have not been te sted in vivo because plaques are too small (by several orders of magnitude) for conventional imaging modalities. We now report in vivo multiphoton las er scanning imaging of thioflavine S-stained senile plaques in the Tg2576 t ransgenic mouse model of Alzheimer's disease to test these biophysical mode ls and show that there is no detectable change in plaque size over extended periods of time. Qualitatively, geometric features remain unchanged over t ime 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 i maging sessions. These results indicate that thioflavine S-positive plaques appear and then are stable, supporting a dynamic feedback model of plaque growth.