Evaluation of an ER Export Signal on an Amyloid Precursor Protein Mutant Associated with Alzheimer's Disease
Bhatt, Aash P.
Alzheimer's Disease (AD) is one of the most common human neurodegenerative disorders. Most early-onset familial AD forms (FADs) have one of four genes, which is the amyloid precursor protein (APP). AmyloId plaques In the brain are an AD hallmark. The primary component of plaque is A𝛽 40-42, an abnormally cleaved peptIde product of APP. APP, a type I transmembrane glycoprotein, matures through the secretory pathway. Endoplasmic reticulum (ER) export signals govern ER-to-Golgi export of several glycoproteins. We proposed that if APP were modified to contain an export signal, it would exhibit altered export and proteolytic properties. The APPswe (Swedish pedigree) mutant causes early-onset FAD with an increase in A𝛽 40-42 production. We assessed whether introducing an ER export signal would influence APPswe processing/proteolysis. DXE (aspartic acid-x-glutamic acid), a known export motif, was introduced to APPswe; its properties were compared to unmodified APPswe. In order to measure possible effects of the DXE export motif on APPswe processing and proteolysis, four cell culture assays were used. These assays measured differences in APPswe expression, A𝛽 peptide production, APP's ectodomain secretion, and C-terminal fragment accumulation. None of these assays revealed significant differences in APPswe expression, processing and proteolysis. Results suggest that DXE motifs are insufficient in directing the export of APPswe; and therefore, may not influence all membrane glycoproteins. Additionally, we propose that the C-terminus of APPswe may have an unidentified ER retention signal and/or an ER retrieval signal. This proposed signal's role in APP biology may add insight into the molecular basis of AD.
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