Evidence for D‐Aspartyl‐β‐Amyloid Secretase Activity in Human Brain

Abstract

Alzheimer disease (AD) is characterized neuropathologically by the presence of senile plaques that are composed of the amyloid-β protein (Aβ). Aβ is an insoluble extracellular deposit consisting of 39–43 amino acids that is cleaved from a larger precursor amyloid-β-precursor protein (β-APP). It has been shown that Aβ 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 β-APP peptide bond containing D-Asp at position 1 of the Aβ protein. In the present study, we report data to support the existence of a putative membrane-bound D-β-secretase that can cleave between L-Met-D-Asp at the 1 position of the Aβ 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.