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FAD mutations in presenilin-1 or amyloid precursor protein decrease the efficacy of a gamma-secretase inhibitor: evidence for direct involvement of PS1 in the gamma-secretase cleavage complex.
Neurobiol Dis. 2000 Dec; 7(6 Pt B):673-81.ND

Abstract

To investigate the mechanism of regulation of Ass production by familial Alzheimer's disease (FAD)-linked presenilin 1 (PS1), we used a cell-free system that allows de novo Ass generation to examine whether PS1 participates directly in the gamma-secretase reaction. Optimal Ass generation in vitro was achieved at mildly acidic pH and could be inhibited by the aspartyl protease inhibitor pepstatin A, consistent with the suggestion that gamma-secretase is an aspartyl protease. Dominant negative mutations of the critical transmembrane aspartates in PS1 or full deletion of PS1 did not alter the maturation of APP in the secretory pathway. Instead, PS1 had a direct effect on the inhibition of Ass production by a designed peptidomimetic inhibitor: the inhibition was significantly less effective in cells expressing FAD-causing mutations in either APP or PS1 than in cells expressing the wild-type proteins. Taken together, these findings suggest that PS1 participates physically in a complex with APP during the gamma-secretase cleavage event.

Authors+Show Affiliations

Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. wxia@rics.bwh.harvard.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11114265

Citation

Xia, W, et al. "FAD Mutations in Presenilin-1 or Amyloid Precursor Protein Decrease the Efficacy of a Gamma-secretase Inhibitor: Evidence for Direct Involvement of PS1 in the Gamma-secretase Cleavage Complex." Neurobiology of Disease, vol. 7, no. 6 Pt B, 2000, pp. 673-81.
Xia W, Ostaszewski BL, Kimberly WT, et al. FAD mutations in presenilin-1 or amyloid precursor protein decrease the efficacy of a gamma-secretase inhibitor: evidence for direct involvement of PS1 in the gamma-secretase cleavage complex. Neurobiol Dis. 2000;7(6 Pt B):673-81.
Xia, W., Ostaszewski, B. L., Kimberly, W. T., Rahmati, T., Moore, C. L., Wolfe, M. S., & Selkoe, D. J. (2000). FAD mutations in presenilin-1 or amyloid precursor protein decrease the efficacy of a gamma-secretase inhibitor: evidence for direct involvement of PS1 in the gamma-secretase cleavage complex. Neurobiology of Disease, 7(6 Pt B), 673-81.
Xia W, et al. FAD Mutations in Presenilin-1 or Amyloid Precursor Protein Decrease the Efficacy of a Gamma-secretase Inhibitor: Evidence for Direct Involvement of PS1 in the Gamma-secretase Cleavage Complex. Neurobiol Dis. 2000;7(6 Pt B):673-81. PubMed PMID: 11114265.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - FAD mutations in presenilin-1 or amyloid precursor protein decrease the efficacy of a gamma-secretase inhibitor: evidence for direct involvement of PS1 in the gamma-secretase cleavage complex. AU - Xia,W, AU - Ostaszewski,B L, AU - Kimberly,W T, AU - Rahmati,T, AU - Moore,C L, AU - Wolfe,M S, AU - Selkoe,D J, PY - 2000/12/15/pubmed PY - 2001/3/3/medline PY - 2000/12/15/entrez SP - 673 EP - 81 JF - Neurobiology of disease JO - Neurobiol Dis VL - 7 IS - 6 Pt B N2 - To investigate the mechanism of regulation of Ass production by familial Alzheimer's disease (FAD)-linked presenilin 1 (PS1), we used a cell-free system that allows de novo Ass generation to examine whether PS1 participates directly in the gamma-secretase reaction. Optimal Ass generation in vitro was achieved at mildly acidic pH and could be inhibited by the aspartyl protease inhibitor pepstatin A, consistent with the suggestion that gamma-secretase is an aspartyl protease. Dominant negative mutations of the critical transmembrane aspartates in PS1 or full deletion of PS1 did not alter the maturation of APP in the secretory pathway. Instead, PS1 had a direct effect on the inhibition of Ass production by a designed peptidomimetic inhibitor: the inhibition was significantly less effective in cells expressing FAD-causing mutations in either APP or PS1 than in cells expressing the wild-type proteins. Taken together, these findings suggest that PS1 participates physically in a complex with APP during the gamma-secretase cleavage event. SN - 0969-9961 UR - https://www.unboundmedicine.com/medline/citation/11114265/FAD_mutations_in_presenilin_1_or_amyloid_precursor_protein_decrease_the_efficacy_of_a_gamma_secretase_inhibitor:_evidence_for_direct_involvement_of_PS1_in_the_gamma_secretase_cleavage_complex_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0969-9961(00)90322-X DB - PRIME DP - Unbound Medicine ER -