Generation of an Apoptotic Intracellular Peptide by γ-Secretase Cleavage of Alzheimer's Amyloid ß Protein Precursor

Abstract

The amyloid ß protein precursor (AßPP) is sequentially processed by ß- and γ-secretases to generate the Aß peptide. The biochemical path leading to Aß formation has been extensively studied since extracellular aggregates of amyloidogenic forms of Aß peptide (Aß42) are considered the culprit of Alzheimer's disease. Aside from its pathological relevance, the biological role of AßPP proteolysis is unknown. Although never previously described, cleavage of AßPP by γ-secretase should release, together with Aß, a COOH-terminal AßPP Intracellular Domain, herein termed AID. We have now identified AID-like peptides in brain tissue of normal control and patients with sporadic Alzheimer's disease and demonstrate that AID acts as a positive regulator of apoptosis. Thus, overproduction of AID may add to the toxic effect of Aß42 aggregates and further accelerate neurodegeneration.