The -amyloid (A) peptide is the major constituent of amyloid plaques in Alzheimer's disease (AD) brain and is likely to play a central role in the pathogenesis of this devastating neurodegenerative disorder. The -secretase, -site amyloid precursor protein cleaving enzyme (BACE1; also called Asp2, memapsin 2), is the enzyme responsible for initiating A generation. Thus, BACE is a prime drug target for the therapeutic inhibition of A production in AD. Since its discovery 10 years ago, much has been learned about BACE. This review summarizes BACE properties, describes BACE translation dysregulation in AD, and discusses BACE physiological functions in sodium current, synaptic transmission, myelination, and schizophrenia. The therapeutic potential of BACE will also be considered. This is a summary of topics covered at a symposium held at the 39th annual meeting of the Society for Neuroscience and is not meant to be a comprehensive review of BACE.BACE: the -secretase in Alzheimer's disease Although the etiology of Alzheimer's disease (AD) is not completely understood, the study of disease genes that cause AD has revealed important clues about the pathogenesis of this disorder. Familial AD (FAD) cases are caused by autosomal dominant mutations in the genes for amyloid precursor protein (APP) and the presenilins (PS1 and PS2) (Sisodia and St George-Hyslop, 2002). These mutations increase production of the 42-aa-long, fibrillogenic form of A (A 42 ), relative to A 40 . In addition, patients with APP gene duplications or individuals with Down's syndrome (trisomy 21), who have increased dosage of the APP gene (located on chromosome 21), develop early-onset AD and overproduce A 42 (Hardy, 2006). These findings, along with a large body of evidence from other sources (Selkoe, 2008), strongly suggest that A 42 plays a central, early role in AD pathogenesis. Thus, therapeutic strategies to lower cerebral A 42 levels are expected to be beneficial for the treatment or prevention of AD.A is produced through the endoproteolysis of APP, a large type 1 transmembrane protein. Cleavage of APP by two proteases, the -and ␥-secretases, is required to liberate A from APP (Tanzi and Bertram, 2005). The -secretase cuts APP first to generate the N terminus of A, thus producing a membrane bound C-terminal fragment called C99. Then, ␥-secretase cleaves C99 to release the mature A peptide. A third protease, ␣-secretase, cuts APP within the A domain, thus precluding A formation.