Alzheimer's disease (AD) is characterized by a progressive deposition of the 4 kDa b-amyloid peptide (Ab) in senile plaques and accumulation of tau protein as neurofibrillary tangles. In normal healthy individuals, Ab peptides are present only in small quantities as soluble monomers that circulate in cerebrospinal fluid and blood. However, in AD patients, their levels are significantly increased and they begin to accumulate as insoluble, fibrillar plaques. Ab is a 40 to 43 amino acid peptide that originates from the proteolytic cleavage of the amyloid precursor protein (APP). Processing of APP in vivo occurs by two major pathways. Cleavage of APP at the N-terminus of the Ab region by b-secretase and at the C-terminus by g-secretases represents the amyloidogenic pathway for processing of APP. The b-secretase cleaves APP between residues Met⁶⁷¹ and Asp⁶⁷² and yields sAAPb and C99 fragments. The b-secretase has also been identified as an aspartyl protease (BACE or Asp-2) of unusual nature. It has a C-terminal transmembrane domain and two active site motifs located in the luminal domain.

APP can also be processed by a-secretase (TACE), which cleaves within the Ab domain between Lys⁶⁸⁷ and Leu⁶⁸⁸ and produces a large soluble a-APP domain and the C-terminal fragment containing P3 and C83.. The latter can then be cleaved by g-secretase at residue 711 or 713 to release P3 fragment. This pathway does not yield Ab peptide. Hence, shunting APP towards the a-secretase pathway may have a beneficial effect in lowering Ab peptide levels.