Generation of an apoptotic intracellular peptide by γ-secretase cleavage of Alzheimer's amyloid β protein precursor

The amyloid β protein precursor (AβPP) is sequentially processed by β- and γ-secretases to generate the Aβ peptide. The biochemical path leading to Aβ formation has been extensively studied since extracellular aggregates of amyloidogenic forms of Aβ peptide (Aβ42) are considered the culprit of Alzheimer's disease. Aside from its pathological relevance, the biological role of AβPP proteolysis is unknown. Although never previously described, cleavage of AβPP by γ-secretase should release, together with Aβ, a COOH-terminal AβPP 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 toxic effect of Aβ42 aggregates and further accelerate neurodegeneration.