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Mutations in APP have independent effects on Abeta and CTFgamma generation.
Neurobiol Dis. 2004 Nov; 17(2):205-18.ND

Abstract

Understanding the molecular mechanism of beta-amyloid (Abeta) generation is crucial for Alzheimer's disease pathogenesis as well as for normal APP function. The transmembrane domain (TM) of APP appears to undergo presenilin-dependent gamma-secretase cleavage at two topologically distinct sites: a site in the middle of the TM domain that is crucial for the generation of Abeta-peptides, and a site close to the cytoplasmic border (S3-like/epsilon site) of the TM domain that leads to production of the APP intracellular domain (CTFgamma/AICD). We demonstrate that, in contrast to the unique effect of familial Alzheimer's disease (FAD) mutations in APP on Abeta42 production, some but not all FAD mutations also affect CTFgamma generation. Furthermore, changes in total CTFgamma levels do not correlate with either an increase or a decrease of any Abeta species, and inhibition of Abeta-peptide formation starting from position +1 (Abeta1-x) does not affect CTFgamma production. These results suggest that cleavage at the gamma40/42- and the S3-like sites can be dissociated, and that APP signaling and Abeta production are not tightly linked.

Authors+Show Affiliations

Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.No 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

15474359

Citation

Hecimovic, Silva, et al. "Mutations in APP Have Independent Effects On Abeta and CTFgamma Generation." Neurobiology of Disease, vol. 17, no. 2, 2004, pp. 205-18.
Hecimovic S, Wang J, Dolios G, et al. Mutations in APP have independent effects on Abeta and CTFgamma generation. Neurobiol Dis. 2004;17(2):205-18.
Hecimovic, S., Wang, J., Dolios, G., Martinez, M., Wang, R., & Goate, A. M. (2004). Mutations in APP have independent effects on Abeta and CTFgamma generation. Neurobiology of Disease, 17(2), 205-18.
Hecimovic S, et al. Mutations in APP Have Independent Effects On Abeta and CTFgamma Generation. Neurobiol Dis. 2004;17(2):205-18. PubMed PMID: 15474359.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mutations in APP have independent effects on Abeta and CTFgamma generation. AU - Hecimovic,Silva, AU - Wang,Jun, AU - Dolios,Georgia, AU - Martinez,Maribel, AU - Wang,Rong, AU - Goate,Alison M, PY - 2003/06/30/received PY - 2004/04/02/revised PY - 2004/04/15/accepted PY - 2004/10/12/pubmed PY - 2004/12/22/medline PY - 2004/10/12/entrez SP - 205 EP - 18 JF - Neurobiology of disease JO - Neurobiol Dis VL - 17 IS - 2 N2 - Understanding the molecular mechanism of beta-amyloid (Abeta) generation is crucial for Alzheimer's disease pathogenesis as well as for normal APP function. The transmembrane domain (TM) of APP appears to undergo presenilin-dependent gamma-secretase cleavage at two topologically distinct sites: a site in the middle of the TM domain that is crucial for the generation of Abeta-peptides, and a site close to the cytoplasmic border (S3-like/epsilon site) of the TM domain that leads to production of the APP intracellular domain (CTFgamma/AICD). We demonstrate that, in contrast to the unique effect of familial Alzheimer's disease (FAD) mutations in APP on Abeta42 production, some but not all FAD mutations also affect CTFgamma generation. Furthermore, changes in total CTFgamma levels do not correlate with either an increase or a decrease of any Abeta species, and inhibition of Abeta-peptide formation starting from position +1 (Abeta1-x) does not affect CTFgamma production. These results suggest that cleavage at the gamma40/42- and the S3-like sites can be dissociated, and that APP signaling and Abeta production are not tightly linked. SN - 0969-9961 UR - https://www.unboundmedicine.com/medline/citation/15474359/Mutations_in_APP_have_independent_effects_on_Abeta_and_CTFgamma_generation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0969-9961(04)00156-1 DB - PRIME DP - Unbound Medicine ER -