Role of presenilin in gamma-secretase cleavage of amyloid precursor protein
- PMID: 10959033
- DOI: 10.1016/s0531-5565(00)00111-x
Role of presenilin in gamma-secretase cleavage of amyloid precursor protein
Abstract
Cerebral accumulation of the amyloid beta-protein (Abeta) is an early and invariant event in the pathogenesis of Alzheimer's disease (AD). Mutations in the presenilin (PS) 1 and 2 genes that increase production of the highly amyloidogenic Abeta(42) are the most common cause of familial AD. Deletion of PS1 in mice reduces Abeta generation, indicating that PS1 mediates the last step in the generation of Abeta from beta-amyloid precursor protein (APP) by the unidentified gamma-secretase. Mutating either of two conserved transmembrane aspartates in PS1 significantly reduced Abeta production and increased the APP C-terminal fragments that are gamma-secretase substrates. These results indicate that PS1 is either a unique diaspartyl cofactor for gamma-secretase or is itself gamma-secretase. Furthermore, studies on the gamma-secretase-like proteolytic processing of Notch and Ire1 suggest a common mechanism for the involvement of PS1 in intramembrane proteolysis of membrane proteins.
Similar articles
-
Genes and mechanisms involved in beta-amyloid generation and Alzheimer's disease.Eur Arch Psychiatry Clin Neurosci. 1999;249(6):266-70. doi: 10.1007/s004060050098. Eur Arch Psychiatry Clin Neurosci. 1999. PMID: 10653281 Review.
-
Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity.Nature. 1999 Apr 8;398(6727):513-7. doi: 10.1038/19077. Nature. 1999. PMID: 10206644
-
Failure of the interaction between presenilin 1 and the substrate of gamma-secretase to produce Abeta in insect cells.J Neurochem. 2002 Oct;83(2):390-9. doi: 10.1046/j.1471-4159.2002.01138.x. J Neurochem. 2002. PMID: 12423249
-
The transmembrane aspartates in presenilin 1 and 2 are obligatory for gamma-secretase activity and amyloid beta-protein generation.J Biol Chem. 2000 Feb 4;275(5):3173-8. doi: 10.1074/jbc.275.5.3173. J Biol Chem. 2000. PMID: 10652302
-
gamma-Secretase inhibitors as molecular probes of presenilin function.J Mol Neurosci. 2001 Oct;17(2):199-204. doi: 10.1385/JMN:17:2:199. J Mol Neurosci. 2001. PMID: 11816793 Review.
Cited by
-
Epigenetics of Alzheimer's disease and frontotemporal dementia.Neurotherapeutics. 2013 Oct;10(4):709-21. doi: 10.1007/s13311-013-0219-0. Neurotherapeutics. 2013. PMID: 24150812 Free PMC article. Review.
-
Cell "self-eating" (autophagy) mechanism in Alzheimer's disease.Mt Sinai J Med. 2010 Jan-Feb;77(1):59-68. doi: 10.1002/msj.20161. Mt Sinai J Med. 2010. PMID: 20101724 Free PMC article. Review.
-
Coenzyme Q10 attenuates beta-amyloid pathology in the aged transgenic mice with Alzheimer presenilin 1 mutation.J Mol Neurosci. 2008 Feb;34(2):165-71. doi: 10.1007/s12031-007-9033-7. Epub 2008 Jan 5. J Mol Neurosci. 2008. PMID: 18181031
-
Workflow and methods of high-content time-lapse analysis for quantifying intracellular calcium signals.Neuroinformatics. 2008 Summer;6(2):97-108. doi: 10.1007/s12021-008-9016-z. Epub 2008 May 28. Neuroinformatics. 2008. PMID: 18506641 Free PMC article.
-
Reactive astrocytes as treatment targets in Alzheimer's disease-Systematic review of studies using the APPswePS1dE9 mouse model.Glia. 2021 Aug;69(8):1852-1881. doi: 10.1002/glia.23981. Epub 2021 Feb 25. Glia. 2021. PMID: 33634529 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
