Intracellular Production of βA4 Amyloid of Alzheimer's Disease: Modulation by Phosphoramidon and Lack of Coupling to the Secretion of the Amyloid Precursor Protein

Abstract

The amyloid precursor protein (APP) undergoes abnormal metabolism in Alzheimer's disease, resulting in the accumulation of βA4 amyloid in the brain. Normal APP metabolism includes the release of a truncated form (sAPP) which has been cleaved at the a-secretase site within the βA4 amyloidogenic domain. However, intact forms of βA4 protein may also be generated by the β- and γ-secretases. Soluble forms of βA4 have been detected in various cell lines and in cerebrospinal fluid. Previous studies of protein kinase C activation have suggested a reciprocal relationship between sAPP secretion and βA4 production and release. We find that phorbol ester activation of protein kinase C in untransfected S..