Evidence for D-aspartyl-beta-amyloid secretase activity in human brain

Alzheimer disease (AD) is characterized neuropathologically by the presence of senile plaques that are composed of the amyloid-beta protein (Abeta). Abeta is an insoluble extracellular deposit consisting of 39-43 amino acids that is cleaved from a larger precursor amyloid-beta-precursor protein (beta-APP). It has been shown that Abeta proteins extracted from amyloid cores of neuritic plaques contain isomerized and/or racemized Asp residues. Therefore, we hypothesized that a specific secretase (s) may exist in the human brain that can cleave a beta-APP peptide bond containing D-Asp at position 1 of the Abeta protein. In the present study, we report data to support the existence of a putative membrane-bound D-beta-secretase that can cleave between L-Met-D-Asp at the 1 position of the Abeta with a pH optimum in the neutral pH range. The specific enzyme activity of soluble extracts from AD samples was 22% higher compared to age-matched controls.