One of the big questions surrounding Alzheimer's disease is whether amyloid plaques are really toxic to neurons. Despite the fact that mutations in AβPP cause AD, the link between amyloid plaques and neuronal loss is considered tenuous, in part because AβPP-transgenic mice do not show overt, widespread neuronal loss. In this week's PNAS online, scientists show that a subset of plaques, namely those that bind the dye thioflavin S, are indeed particularly damaging in vivo.
Led by Brad Hyman at Massachusetts General Hospital in Boston, researchers there and at Boston University, the University of Minnesota, Minneapolis, and the Nathan Kline Institute, Orangeburg, New York, borrowed a technique from condensed matter physics to examine the neuronal environment surrounding Aβ deposits. The authors used this "density mapping" technique to superimpose confocal microscope images of neurons, immunogenic Aβ plaques, and plaques that take up the thioflavin dye.
When mapping post-mortem tissue sections from human AD brains and from transgenic mice expressing mutant forms of human Aβ PP, the scientists found that the greatest ablation of neurons occurred around plaques that were 20-30 microns in diameter; larger and smaller plaques were less damaging. In addition, both very dense plaques and plaques that stained with hioflavin S appeared most deleterious. In mice, those deposits that took up the dye were also the densest.
The authors again turned to mathematical techniques to figure out what happens to neurons near these deposits. Do plaques just muscle neurons out of the way, or are the neurons actually dying? A molecular dynamics algorithm provided the answer, showing that data from the mapping experiments was best explained by a toxic plaque model. Furthermore, models suggest that the damage only extends to the limits of the plaque, in other words, neurons outside the plaque radius are not being poisoned by leeching toxic amyloid.
The data confirm prior cell culture experiments suggesing that fibrillar Aβ, the form that binds thioflavin-S, is toxic to neurons, while the soluble form is not. Still, the authors point out that this does not fully explain the pathology of AD because neuronal loss is found to be much more widespread in the disease state than are thioflavin-positive plaques.—Tom Fagan
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- Urbanc B, Cruz L, Le R, Sanders J, Ashe KH, Duff K, Stanley HE, Irizarry MC, Hyman BT. Neurotoxic effects of thioflavin S-positive amyloid deposits in transgenic mice and Alzheimer's disease. Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):13990-5. PubMed.