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

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.

Altered Balance of Reelin Proteolytic Fragments in the Cerebrospinal Fluid of Alzheimer’s Disease Patients

“…Interestingly, apoE3 and apoE4 consistently inhibited reelin from binding to VLDLR and apoER2; this study also indicated that apoE interfered with the ability of reelin to activate a Dab1-dependent signaling pathway [ 12 ]. A later study also saw that, unlike reelin, apoE failed to elevate apoER2 processing [ 65 ], whereas others have found that the Dab1-dependent pathway was activated by apoE [ 66 ] and that apoE and apoER2 co-localized in endosomes [ 67 ].…”

Apolipoprotein E4 inhibits autophagy gene products through direct, specific binding to CLEAR motifs

“…T98G cells were obtained from American Type Culture Collection. Stable transformants were generated as described previously by Wang et al [23]. Recombinant apoE was prepared under native conditions with the intention of retaining any lipid content present.…”

“…ApoE was purified from conditioned medium of T98G-apoE3-expressing or T98G-apoE4-expressing cells, as described in Wang [23]. ApoE proteins (50 ng) were mixed with BSA (5 μg) and incubated under conditions described by Mao et al [27] with a 32 P-labeled dsDNA probe containing either the CLEAR sequence (5′-GTA GGT CAC GTG ACC GGG-3′) or a scrambled sequence (5′-GTA GGT CTG CAG ACC GGG-3′).…”

The Reelin Receptors Apolipoprotein E receptor 2 (ApoER2) and VLDL Receptor

“…In addition to Reelin itself, gene polymorphism studies point to the possibility that variations of the ApoER2 gene are also associated with development of AD [ 131 ]. ApoER2 association to AD was also recently reported by a study showing that ApoER2 trafficking and processing is influenced by mutations in the presenilin 1 gene identified as risk factor for familial AD [ 132 ]. Indeed, the processing of ApoER2 is changed in AD patients in a way that less ApoER2-CTF fragments are produced [ 133 ].…”