One of the limitations in studying the pathogenic role of amyloid plaque deposition is the fact that conventional methods allow microscopic analysis only of postmortem tissue, which can provide only a single snapshot of a process that is clearly dynamic and evolves over a long time span. An approach to overcoming this constraint was presented by Rich Christie (120.11), who reported on the use of two-photon imaging to visualize plaque formation in Tg2576 mice while they are still alive. The technique involves labeling plaques with thioflavin S and then imaging the brain of the mouse by placing the animal on the microscope stage and visualizing the plaques through multiphoton microscopy. (To protect the brain, the skull is thinned down to provide a "window" for imaging without a complete craniotomy.) The images are quite impressive and the evidence indicates that it is possible to reimage the same field in successive sessions over a period of several months.
Once the feasibility of the method was established, the first question addressed was whether plaques are stable or increase in size over time. The evidence so far indicates that the majority of plaques are remarkably stable in size. Although occasional "outliers" show evidence of increases in size, these are in the minority. In addition, Christie provided a good example of new plaque formation within a field that had been imaged on several occasions. Although this evidence appears to suggest that amyloid plaques form precipitously and then remain static, previously published work from this laboratory, led by Bradley Hyman, indicates that the relatively stable size of plaques results from an equilibrium state between an aggregation and degradation process. The in vivo two-photon technique should provide additional insights into the dynamics of plaque formation that, in turn, could reveal aspects of AD. What is more, they could offer a literal window onto the effects of "plaque-busting" therapies in transgenic mouse models.—Keith Crutcher
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