That β-amyloid plays a central role in the pathogenesis of Alzheimer's disease is doubted by few investigators. However, pinning down the exact contribution amyloid makes has been remarkably difficult to accomplish. Novel hypotheses are becoming rarer but the series of reports from investigators at the R.W. Johnson Pharmaceutical Research Institute and collaborators at UMDNJ certainly falls into this category. Two of the presentations today provided evidence that amyloid may bind to α7-nicotinic cholinergic receptors (a7nAChR). The first, given by Hoau Yan Wang (12.2), noted that a7nAChR are present in plaques, co-localizing with Aß42. Aß42 also shows high affinity binding to cells transfected with a7nAChR, binding that is inhibited by bungarotoxin. In addition, co-precipitation experiments demonstrate that the level of a7nAChR/Aß42 complex is over ten times greater in AD tissue as compared with control tissue. Aß40 has similar properties but with lower affinity.

The second talk, given by Daniel Lee (12.3), provided evidence that the interaction of amyloid with 7nAChR leads to tau phosphorylation. Three different phosphorylation sites were examined, serine 202, threonine 231 and threonine 181. The latter two sites appear to be phosphorylated more rapidly than the serine site. Generally similar results were obtained with guinea pig hippocampal synaptosomes. The phosphorylation was inihibited by bungarotoxin but not by α -conotoxin or macamylamine. In addition, there is some indication that amyloid toxicity can be partly blocked by bungarotoxin. Collectively, these results provide an interesting connection between the amyloid hypothesis and tau pathology. If additional studies confirm the high affinity binding of amyloid to nicotinic receptors and the phosphorylation effects, this provides a new framework for understanding the role of amyloid in AD.

A third presentation, by Michael D'Andrea (120.10), referred to the earlier talks demonstrating the binding of amyloid to nicotinic receptors but focused on the question of plaque origin. He noted that plaques are distributed in specific cortical laminae and have restricted sizes. He also noted that amyloid staining can be found in some pyramidal neurons, leading to the hypothesis that intracellular amyloid may serve as a nidus for the development of dense-core plaques. Using the same transfected cell line described by Wang and Lee, fluo-Aß42 was used to follow the intracellular accumulation of amyloid (presumably via the nicotinic receptors). There appears to be distortion and eventual disruption of cells in which the amyloid accumulates. This observation led to further consideration of the evidence that disrupted neurons may serve to seed plaque formation. A variety of neuronal markers, as well as nucleic acid, are found in the plaque cores. Interestingly, a fairly good correlation was also found between the size of plaques and the size of the surrounding pyramidal cells. Although the studies are largely based on correlations, the possibility that intraneuronal amyloid (perhaps accumulated through binding to nicotinic cholinergic receptors) may ultimately seed plaques is an intriguing suggestion.—Keith Crutcher


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