The endocytotic pathway is required for increased Aβ42 secretion during apoptosis

Secretion and progressive cerebral accumulation of β-amyloid peptides (Aβ), which derive by endoproteolytic ('amyloidogenic') processing of β-amyloid precursor protein (APP), are felt to represent collectively an early and necessary event in the pathogenesis of Alzheimer's disease. APP amyloidogenic processing can occur via secretory or endocytotic pathways, but the relative contribution of these pathways to Aβ secretion remains to be established. The effect of apoptosis on amyloidogenic processing and Aβ secretion similarly is incompletely understood. We tested the hypothesis that APP processing by the endocytotic pathway represents a stress-related neural cell response, by comparing Aβ secretion after induction of apoptosis in PC12 cells transfected either for endocytosis-competent or -deficient APP. Newly prepared adenoviral vectors encompassing targeted mutagenesis of the cytoplasmic tail YENP tetrapeptide sequence, which serves as the principal APP internalization signal, were used to express endocytosis-deficient holoprotein. We report that the endocytotic pathway is required for the generation and secretion of Aβ42, and that secretion of this neurotoxic peptide increases significantly during apoptosis. We demonstrate additionally that more Aβ40 apparently is generated in secretory compartments during apoptosis when APP processing by the endocytotic pathway is impaired.