Multiphoton microscope tracks plaques in mouse model

Long considered a sentinel factor for Alzheimer's disease, beta-amyloid proteins can accumulate in the brain in aggregations called senile plaques with amazing speed, affecting neurodegeneration just as readily, according to researchers at Harvard Medical School.Using in vivo multiphoton microscopy, Dr. Bradley Hyman and coleagues tracked the deposition of beta-amyloid plaques in the brains of transgenic mice. They were surprised to find that plaques formed extraordinarily quickly over the course of 24 hours. Within one to two days, the plaques appear to cause neurodegeneration to axons, dendrites, and neuroprotective cells. Immune defense cells (microglia) activate and move to the sites of the new plaques. Because the plaque formations did not change in size over days and weeks of imaging, Hyman proposed that the brain may be taking action to limit their growth. The paper points out, however, that plaque formation is rare. After daily and weekly imaging, 26 new plaques were found in 14 animals over 238 sites, imaged a total of 1285 times. Results were published in Nature (2008;451(7179):720-724).Hyman credits the technological advancement of the multiphoton microscope for providing a precise in vivo record of the formation of amyloid plaque and its effects on the brain.

The researchers sequentially imaged the mice using several fluorescent dyes:

• methoxy-X04, a compound that crosses the blood-brain barrier and binds to amyloid plaques
• yellow fluorescence protein for imaging neurons, axons, and dendrites
• Texas Red dextran for imaging blood vessels

The imaging technique is unique in providing an in vivo "video" of events, according to Hyman. His results give more credence to developing drugs and therapies that will reduce amyloid plaques.

While praising the research, Dr. Chet Mathis, a professor of radiology and director of the PET facility at the University of Pittsburgh, cautioned that a mouse model differs from humans. "This is not Alzheimer's disease," Mathis said. "It's a model of Alzheimer's disease in a mouse. One of the big differences with respect to these plaques is that they seem to appear in humans over the course of 50 to 80 years. They develop over a slower time course. I'm just a little skeptical that it's totally translatable to the human condition because of the differences."More research is required about what forms of beta-amyloid do the most damage, Mathis said. The Harvard study focuses on insoluble beta-amyloid in the form of plaques, but some evidence from mouse models shows that soluble beta-amyloid protein not in the plaques, but rather in solution in the extracellular fluids, is more toxic on a per-molecule basis.For more information from the Diagnostic Imaging archives:

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