FIGURE 1. Plaques and tangles in Alzheimer's disease.

Amyloid plaques contain the A peptide, which is produced from the amyloid precursor protein (APP). Cleavage of APP at one point (not shown) generates a carboxy-terminal fragment. This is then severed by the -secretase complex (which consists of at least four proteins¹⁰ — presenilin-1, APH-1, PEN-2 and nicastrin), producing A. Tangles are produced from hyperphosphorylated tau protein, possibly by means of the enzyme glycogen synthase kinase-3 (GSK-3). GSK-3 also regulates phosphorylation of -catenin (which can bind presenilin-1). Phiel et al.¹ find that GSK-3 might also regulate — either directly or indirectly — the cleavage of APP carboxy-terminal fragments. They show that lithium and kenpaullone (two GSK-3 inhibitors), as well as small interfering RNAs that prevent GSK-3 expression, inhibit A production. So, GSK-3 inhibitors might interfere with the generation of both amyloid plaques and tangles in Alzheimer's disease. The precise roles of the two forms of GSK-3, and , are unknown.