Identification of the Multicatalytic Enzyme as a Possible γ-Secretase for the Amyloid Precursor Protein

One of the main components of the senile plaques in brain tissue from patients with Alzheimer′s disease is the β-amyloid peptide. This peptide is proteolytically cleaved from the amyloid precursor protein by the action of at least two proteases, a β-secretase which generates the N-terminus and a γ-secretase which generates the C-terminus. Neither of these proteases have been identified. To identify proteases that are candidates for the γ-secretase we synthesized a small fluorescent peptide substrate containing the amino acids comprising the C-terminus of the longest β-amyloid peptide identified. This substrate is hydrolyzed by a single activity in homogenates from both cells and brain tissue and we have demonstrated that this activity is the multicatalytic enzyme or proteasome. Furthermore, using specific inhibitors, we have demonstrated that the fluorescent substrate is hydrolyzed by the chymotrypsin-like activity of the multicatalytic enzyme.