Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Xia, W. et al.

Xia, Ray, Ostaszewski, Rahmati, Kimberly, Wolfe, Zhang, Goate, Selkoe,

Presenilin complexes with the C-terminal fragments of amyloid precursor protein at the sites of amyloid beta-protein generation.

An unusual intramembranous cleavage of the beta-amyloid precursor protein (APP) by gamma-secretase is the final step in the generation of amyloid beta-peptide (Abeta). Two conserved aspartates in transmembrane (TM) domains 6 and 7 of presenilin (PS) 1 are required for Abeta production by gamma-secretase. Here we report that the APP C-terminal fragments, C83 and C99, which are the direct substrates of gamma-secretase, can be coimmunoprecipitated with both PS1 and PS2. PS/C83 complexes were detected in cells expressing endogenous levels of PS. The complexes accumulate when gamma-secretase is inactivated either pharmacologically or by mutating the PS aspartates. PS1/C83 and PS1/C99 complexes were detected in Golgi-rich and trans-Golgi network-rich vesicle fractions. In contrast, complexes of PS1 with APP holoprotein, which is not the immediate substrate of gamma-secretase, occurred earlier in endoplasmic reticulum-rich vesicles. The major portion of intracellular Abeta at steady state was found in the same Golgi/trans-Golgi network-rich vesicles, and Abeta levels in these fractions were markedly reduced when either PS1 TM aspartate was mutated to alanine. Furthermore, de novo generation of Abeta in a cell-free microsomal reaction occurred specifically in these same vesicle fractions and was markedly inhibited by mutating either TM aspartate. Thus, PSs are complexed with the gamma-secretase substrates C83 and C99 in the subcellular locations where Abeta is generated, indicating that PSs are directly involved in the pathogenically critical intramembranous proteolysis of APP.[1]

References

Presenilin complexes with the C-terminal fragments of amyloid precursor protein at the sites of amyloid beta-protein generation. Xia, W., Ray, W.J., Ostaszewski, B.L., Rahmati, T., Kimberly, W.T., Wolfe, M.S., Zhang, J., Goate, A.M., Selkoe, D.J. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]

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