Presenilin structure in mechanisms leading to Alzheimer's disease.
Molecular genetic studies of familial Alzheimer's disease by 1995 had clearly implicated three proteins as critical to Alzheimer's disease (AD), the amyloid-beta protein precursor (AbetaPP) and the two homologous presenilins, PS-1 and PS-2. To account for the roles of these proteins in AD, we had proposed that as an early and critical step in the mechanisms that lead to AD, the PS on the surface of a brain cell engages in a specific receptor-ligand intercellular interaction with AbetaPP on the surface of a neighboring cell. This cell-cell interaction is required to trigger off a cascade of processes that lead to the production of amyloid-beta (Abeta) from AbetaPP, leading to AD. At about this time, however, many established AD researchers had obtained data that appeared to disagree with our proposed mechanism. Their immediate objections to our proposal were based on their conclusions that 1) The PS proteins were exclusively intracellular, and were not expressed at the cell surface, and 2) The topography of the PS proteins in intracellular membranes exhibits either 6 or 8-TM spanning domains, not 7. Here we discuss the evidence for the 6-TM, 7-TM, 8-TM and other models of PS topography and offer possibilities for the differences in interpretation of the various sets of data. We review the experimental demonstration of the cell-surface expression and the 7-TM structure of PS, the functional consequences of this structure, and the findings that PS-1 and PS-2 are members of the superfamily of 7-TM heterotrimeric G-protein coupled receptors (GPCRs).
Dewji
Nazneen N
NN
Department of Medicine, Mail code 0681, 9500 Gilman Drive, La Jolla, CA 92093, USA. ndewji@ucsd.edu
D000544:Alzheimer Disease / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000276:immunology; D001921:Brain / Q000378:metabolism; D005455:Fluorescent Antibody Technique / Q000379:methods; D006801:Humans; D053764:Presenilin-1 / Q000276:immunology / Q000378:metabolism; D053766:Presenilin-2 / Q000276:immunology / Q000378:metabolism; D053763:Presenilins / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D000911:Antibodies, Monoclonal; D053764:Presenilin-1; D053766:Presenilin-2; D053763:Presenilins; D043562:Receptors, G-Protein-Coupled