|In search of the “β Bang”
The evidence strongly favors a crucial role of the peptide Aβ in the pathogenesis of Alzheimer’s disease (AD). In vitro studies have nicely illuminated the mechanics of polymerization and fibrillization of Aβ and other proteopathic molecules, and the aggregation process has been shown to be strongly influenced by protein concentration. In vivo, Aβ deposition can be accelerated by increased Aβ production, for example, in familial (genetic) AD, Down’s syndrome, in AβPP-overexpressing mice, or following head injury. In many cases of AD, however, a genetic or environmental contribution is not apparent, and in no instance has the actual prime mover of protein polymerization in vivo been identified. Furthermore, the global levels of Aβ in normal brain are well below those needed to achieve the critical polymerization threshold that is seen in vitro. This impediment to aggregation might be overcome by a focal accrual of protein (such as in membranes and/or organelles) or by the action of pathological chaperone molecules that promote Aβ aggregation....