Presenilin 1 mutations influence processing and trafficking of the ApoE receptor apoER2

• Published in: Neurobiology of aging Vol. 49; pp. 145 - 153
• Main Authors: Wang, Wei, Moerman-Herzog, Andrea M, Slaton, Arthur, Barger, Steven W
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2017
• Subjects: Alzheimer Disease - genetics; Alzheimer's disease; Amyloid Precursor Protein Secretases - physiology; Animals; ApoER2; Cell Adhesion Molecules, Neuronal; Cells, Cultured; Extracellular Matrix Proteins; Gene Expression; Internal Medicine; LDL-Receptor Related Proteins - genetics; LDL-Receptor Related Proteins - metabolism; Lipoprotein receptor; Mice, Transgenic; Mutation; Nerve Tissue Proteins; Neurology; Presenilin; Presenilin-1 - genetics; Presenilin-1 - physiology; Protein processing; Protein trafficking; Serine Endopeptidases; γ-Secretase; APP; LRP1; DMSO; N-methyl D-aspartate; double knockout; LTP; mouse embryonic fibroblast; PS1; ApoE receptor 2; dimethyl sulfoxide; amyloid precursor protein; LDL; presenilin; NMDA; ApoE; carboxyterminal fragment; DAPT; SR; eukaryotic-optimized green fluorescent protein; N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester; eGFP; protein trafficking; AD; Alzheimer’s disease; apoER2; protein processing; FAD; DKO; presenilin 1; familial AD; sheddase remnant; low-density lipoprotein; MEF; lipoprotein receptor; CTF; LDL receptor-related protein 1; apolipoprotein E; γ-secretase; long-term potentiation; Lipoprotein receptor; Presenilin; Protein processing; Alzheimer's disease; ApoER2; γ-Secretase; Protein trafficking
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2016.10.005

Abstract Presenilin (PS)-1 is an intramembrane protease serving as the catalytic component of γ-secretase. Mutations in the PS1 gene are the most common cause of familial Alzheimer’s disease (FAD). The LDL-receptor family member apoER2 is a γ-secretase substrate that has been associated with AD in several ways, including acting as a receptor for apolipoprotein E. ApoER2 is processed by γ-secretase into a C-terminal fragment (γ-CTF) that appears to regulate gene expression. FAD PS1 mutations were tested for effects on apoER2. PS1 mutation R278I showed impaired γ-secretase activity for apoER2 in the basal state or after exposure to Reelin. PS1 M146V mutation permitted accumulation of apoER2 CTFs after Reelin treatment, while no difference was seen between wild-type (WT) and M146V in the basal state. PS1 L282V mutation, combined with the γ-secretase inhibitor DAPT, greatly reduced the cell-surface levels of apoER2 without affecting total apoER2 levels, suggesting a defect in receptor trafficking. These findings indicate that impaired processing or localization of apoER2 may contribute to the pathogenic effects of FAD mutations in PS1.