Figure 1a. Two theories of how damage occurs in AD. (a) From outside the cell, amyloid ß peptides secreted by brain cells are normally soluble, and any excess is cleared away. When these peptides become insoluble, however, they collect in the space between cells. Amyloid fibrils are "herded" together by chaperone proteins. The large plaques that form then damage brain cells and attract reactive cells, microglia and astrocytes, which cause further damage. (b) From inside the cell, tau proteins, which normally stabilize microtubules in brain cells, undergo abnormal chemical changes and assemble into spirals called paired helical filaments, thus creating tangles that disrupt cell functions and lead to cell death. (Images courtesy of Dr John Trojanowski and Dr Virginia M. Y. Lee, University of Pennsylvania Medical Center, Philadelphia.)