ABSTRACT
T he neurodegeneration in Alzheimer’s disease (AD) may be caused by deposition of amyloid ß peptide (Aß) in plaques in brain tissue (amyloid hypothesis). Mechanisms of Aß production in the brain have been the subject of considerable interest. Several factors regulate processing of amyloid precursor protein (APP), which is cleaved by three types of membrane-bound proteases designated α-ß-and γ-secretases. Although we are only begin ning to understand their functions, the discovery of nonamyloidogenic a-secretase has already provided some answers to longstanding questions of Alzheimer drug development. Here we summarize recent advances in the identification of APP a-secretases. Pharmacological up-regulation γ-secretases should provide rational drug design for Alzheimer’s disease.
