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Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein.
Nature. 1998 Jan 22; 391(6665):387-90.Nat

Abstract

Point mutations in the presenilin-1 gene (PS1) are a major cause of familial Alzheimer's disease. They result in a selective increase in the production of the amyloidogenic peptide amyloid-beta(1-42) by proteolytic processing of the amyloid precursor protein (APP). Here we investigate whether PS1 is also involved in normal APP processing in neuronal cultures derived from PS1-deficient mouse embryos. Cleavage by alpha- and beta-secretase of the extracellular domain of APP was not affected by the absence of PS1, whereas cleavage by gamma-secretase of the transmembrane domain of APP was prevented, causing carboxyl-terminal fragments of APP to accumulate and a fivefold drop in the production of amyloid peptide. Pulse-chase experiments indicated that PS1 deficiency specifically decreased the turnover of the membrane-associated fragments of APP. As in the regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor, PS1 appears to facilitate a proteolytic activity that cleaves the integral membrane domain of APP. Our results indicate that mutations in PS1 that manifest clinically cause a gain of function and that inhibition of PS1 activity is a potential target for anti-amyloidogenic therapy in Alzheimer's disease.

Authors+Show Affiliations

Experimental Genetics Group, Flemish Institute for Biotechnology (VIB4), Center for Human Genetics, K.U.Leuven, Belgium. Bart.Destrooper@med.kuleuven.ac.beNo affiliation info availableNo 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

Language

eng

PubMed ID

9450754

Citation

De Strooper, B, et al. "Deficiency of Presenilin-1 Inhibits the Normal Cleavage of Amyloid Precursor Protein." Nature, vol. 391, no. 6665, 1998, pp. 387-90.
De Strooper B, Saftig P, Craessaerts K, et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature. 1998;391(6665):387-90.
De Strooper, B., Saftig, P., Craessaerts, K., Vanderstichele, H., Guhde, G., Annaert, W., Von Figura, K., & Van Leuven, F. (1998). Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature, 391(6665), 387-90.
De Strooper B, et al. Deficiency of Presenilin-1 Inhibits the Normal Cleavage of Amyloid Precursor Protein. Nature. 1998 Jan 22;391(6665):387-90. PubMed PMID: 9450754.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. AU - De Strooper,B, AU - Saftig,P, AU - Craessaerts,K, AU - Vanderstichele,H, AU - Guhde,G, AU - Annaert,W, AU - Von Figura,K, AU - Van Leuven,F, PY - 1998/2/5/pubmed PY - 2001/3/23/medline PY - 1998/2/5/entrez SP - 387 EP - 90 JF - Nature JO - Nature VL - 391 IS - 6665 N2 - Point mutations in the presenilin-1 gene (PS1) are a major cause of familial Alzheimer's disease. They result in a selective increase in the production of the amyloidogenic peptide amyloid-beta(1-42) by proteolytic processing of the amyloid precursor protein (APP). Here we investigate whether PS1 is also involved in normal APP processing in neuronal cultures derived from PS1-deficient mouse embryos. Cleavage by alpha- and beta-secretase of the extracellular domain of APP was not affected by the absence of PS1, whereas cleavage by gamma-secretase of the transmembrane domain of APP was prevented, causing carboxyl-terminal fragments of APP to accumulate and a fivefold drop in the production of amyloid peptide. Pulse-chase experiments indicated that PS1 deficiency specifically decreased the turnover of the membrane-associated fragments of APP. As in the regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor, PS1 appears to facilitate a proteolytic activity that cleaves the integral membrane domain of APP. Our results indicate that mutations in PS1 that manifest clinically cause a gain of function and that inhibition of PS1 activity is a potential target for anti-amyloidogenic therapy in Alzheimer's disease. SN - 0028-0836 UR - https://www.unboundmedicine.com/medline/citation/9450754/Deficiency_of_presenilin_1_inhibits_the_normal_cleavage_of_amyloid_precursor_protein_ L2 - https://doi.org/10.1038/34910 DB - PRIME DP - Unbound Medicine ER -