Stable Association of Presenilin Derivatives and Absence of Presenilin Interactions with APP

Mutations in two related genes,presenilin 1andpresenilin 2(PS1andPS2), cosegregate with Alzheimer's disease. PS1 and PS2 are highly homologous polytopic membrane proteins that are subject to endoproteolytic cleavagein vivo.The resulting N- and C-terminal derivatives are the preponderant PS-rela...

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Bibliographic Details
Published in:Neurobiology of disease 1998, Vol.4 (6), p.438-453
Main Authors: Thinakaran, Gopal, Regard, Jean B., Bouton, Christopher M.L., Harris, Christie L., Price, Donald L., Borchelt, David R., Sisodia, Sangram S.
Format: Article
Language:English
Subjects:
Alzheimer Disease - metabolism
Amyloid beta-Protein Precursor - analysis
Amyloid beta-Protein Precursor - immunology
Amyloid beta-Protein Precursor - metabolism
Animals
Detergents
Epitopes - analysis
Membrane Proteins - genetics
Membrane Proteins - immunology
Membrane Proteins - metabolism
Mice
Mutation
Neuroblastoma
Peptide Fragments - immunology
Polyethylene Glycols
Precipitin Tests
Presenilin-1
Presenilin-2
Tumor Cells, Cultured
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Summary:Mutations in two related genes,presenilin 1andpresenilin 2(PS1andPS2), cosegregate with Alzheimer's disease. PS1 and PS2 are highly homologous polytopic membrane proteins that are subject to endoproteolytic cleavagein vivo.The resulting N- and C-terminal derivatives are the preponderant PS-related species that accumulate in cultured cells and tissue. In earlier studies, we demonstrated that PS1 N- and C-terminal derivatives accumulate to 1:1 stoichiometry and that the absolute levels of fragments are established by a tightly regulated and saturable mechanism. These findings led to the suggestion that the levels of PS1 derivatives might be determined by their association with limiting cellular components. In this study, we usein situchemical cross-linking and coimmunoprecipitation analyses to document that the N- and C-terminal derivatives of either PS1 or PS2 can be coisolated. Moreover, and in contrast to published reports which documented that PS1 and PS2 form stable heteromeric assemblies with the β-amyloid precursor protein (APP), we have failed to provide evidence for physiological complexes between PS1 and PS2 holoproteins or their derivatives with APP.
ISSN:0969-9961
1095-953X
DOI:10.1006/nbdi.1998.0171