Last year, Brad Hyman’s group reported on their ability to image amyloid plaques in the brains of live PDAPP Tg mice. Plaques could be detected as deep as 200 microns and the same plaques could be imaged over the course of weeks using a multiphoton laser scanning microscope (see Abstract 120.11 from 1999). With all the recent fervor over vaccination treatments for Alzheimer’s disease, it was only natural for them to turn their attention to the effects of immunization on "living" plaques. While there is little doubt that active immunization with β-amyloid in mice Tg for APP can inhibit plaque formation and likely promote the clearance or partial clearance of preexisting amyloid deposits as well, over what time frame do these events occur, and can we watch the process happen? Bacskai, Hyman and colleagues presented data on the reliability and reproducibility of imaging plaques in live PDAPP mice and the effects of passive administration of anti-beta-amyloid antibodies (Abstract 397.2). The process uses high resolution near infrared imaging to yield images with a 1 micron voxel resolution as deep as 200 microns below the cortical surface. Mice are surgically prepped by removing a small piece of the skull over the region of interest to expose the cortical surface.
Using fluorescein injected i.v. to allow imaging of blood vessels, and thioflavine to image β-pleated amyloid deposits, they were able to find the same volume of tissue for more than a month and observe stable plaques. In a set of animals, 65 thioflavine-positive plaques were detected and antibodies against β-amyloid (10D5) were applied to the surface of the brain. Within three days, 70 percent of these plaques were cleared. A control antibody failed to clear any plaques.
In a separate experiment, anti-10D5 tagged with FITC was applied to both detect diffuse plaques and induce clearance. Again, over three days the diffuse plaques were cleared. There was concern that the "diffuse" experiment is not as clean as the fibrillar experiments because the same IgG used to detect the plaques was used to induce clearance and redetect the plaques.
It is possible (but not likely), that the detection step would be hindered by already present IgG. However, the thioflavine-based experiments do not have this issue and one would think those fibrillar plaques would be harder to clear than diffuse plaques. In addition, animals were sacrificed and sections taken of the fields imaged. In a side view showing the depth of cortex, one could clearly see a concave zone of cortex below the imaging window that was devoid of plaques. Adjacent sections showed a cluster of tomato-lectin positive microglia within the zone of cleared plaques. Thus, both diffuse and compact plaques can be cleared via passive immunotherapy.
Great news for those of use who worry about an autoimmune response in man. Of course, there is still the issue of activating the immune system and cytokine responses in man versus mice, where APP is under a different promoter. In man, an enhanced inflammatory response may increase the production of APP.—Brian J Cummings
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