The Role of APP Processing and Trafficking Pathways in the Formation of Amyloid β‐Proteina

作者：Dennis J. Selkoe, Tsuneo Yamazaki, Martin Citron, Marcia Berman Podlisny, Edward H. Koo, David B. Teplow, Christian Haass · 发表于：Annals of the New York Academy of Sciences · 年份：1996 · DOI：10.1111/j.1749-6632.1996.tb34401.x · 被引用次数：249 · 研究领域：Alzheimer's disease research and treatments、Prion Diseases and Protein Misfolding、Amyloidosis: Diagnosis, Treatment, Outcomes

The amyloid beta-protein (A beta) is a proteolytic fragment of the beta-amyloid precursor protein (beta APP). We previously reported the constitutive secretion of A beta peptides from a variety of cells expressing beta APP under normal culture conditions. These endogenously produced A beta peptides have heterogeneous N- and C-termini that vary as a function of beta APP missense mutations. Treatment of A beta-secreting cells with agents that alter intravesicular pH showed that an acidic compartment is required for proper A beta generation. One such compartment appears to be the endosome. Immunolabeling of cell-surface beta APP in living neurons and non-neuronal cells directly demonstrated the endocytosis of the protein and its rapid recycling (within 5-10 minutes) to the cell surface, as well as the trafficking of some beta APP to lysosomes. Expression of beta APP with various deletions of the cytoplasmic domain, including the NPTY motif, leads to decreased internalization and an associated decrease in the production of A beta peptides that begin at the usual asp1 start site. These and other data suggest that A beta production begins with cleavage of beta APP by a still unknown protease(s) (beta-secretase[s]) at the met-asp bond proceeding the A beta N-terminus and that this occurs in part in early endosomes. To characterize the substrate requirements of beta-secretase, beta APP was mutagenized by placing stop codons within or at the end of the transmembrane domain or substitu...