The neurotoxic amyloid β-peptide (Aβ) is a highly hydrophobic peptide, which aggregates to form oligomers. If these oligomers aggregate further, they start forming fibers, which eventually precipitate and accumulate in amyloid plaques, as defined in Alzheimer’s disease. Generation of Aβ occurs by processing of the β-amyloid precursor protein (APP) via proteases called secretases. Three secretases are known, α-, β-, and γ-secretase. While β- and γ-secretase mediate the amyloidogenic cleavage events, α-secretase on the contrary prevents Aβ generation by cleaving APP in the middle of the Aβ domain. β-Secretase (EC 3.4.23.46; also called BACE-1 for β-site APP-cleaving enzyme) was identified as a type 1 transmembrane protein containing aspartyl protease activity and belongs to the pepsin family of aspartyl proteases, but defines a novel subgroup of membrane-associated hydrolases. BACE-1 mediates the primary amyloidogenic cleavage of APP and generates a membrane-bound APP C-terminal fragment (APP CTFβ), which is the immediate precursor for the intramembraneous γ-secretase cleavage. In contrast, BACE-2 exhibits an α-secretase-like activity, which cleaves APP in the middle of the Aβ domain at amino acids 19 and 20. Thus, BACE-2 does not contribute to the amyloidogenic processing of APP, which is consistent with the complete lack of Aβ generation in a BACE-1 knockout[1],[2].