Regulated intramembrane proteolysis of amyloid precursor protein and regulation of expression of putative target genes.

Neuronal Cell Biology and Gene Transfer, CME, Flanders Interuniversity Institute for Biotechnolog, VIB4, and Katholieke Universiteit Leuven, Herestraat 49, Leuven 3000, Belgium.
EMBO Reports (Impact Factor: 7.86). 08/2006; 7(7):739-45. DOI: 10.1038/sj.embor.7400704
Source: PubMed

ABSTRACT gamma-Secretase-dependent regulated intramembrane proteolysis of amyloid precursor protein (APP) releases the APP intracellular domain (AICD). The question of whether this domain, like the Notch intracellular domain, is involved in nuclear signalling is highly controversial. Although some reports suggest that AICD regulates the expression of KAI1, glycogen synthase kinase-3beta, Neprilysin and APP, we found no consistent effects of gamma-secretase inhibitors or of genetic deficiencies in the gamma-secretase complex or the APP family on the expression levels of these genes in cells and tissues. Finally, we demonstrate that Fe65, an important AICD-binding protein, transactivates a wide variety of different promoters, including the viral simian virus 40 promoter, independent of AICD coexpression. Overall, the four currently proposed target genes are at best indirectly and weakly influenced by APP processing. Therefore, inhibition of APP processing to decrease Abeta generation in Alzheimer's disease will not interfere significantly with the function of these genes.

1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Since the original publication describing the illness in 1907, the genetic understanding of Alzheimer's disease (AD) has advanced such that it is now clear that it is a genetically heterogeneous condition, the subtypes of which may not uniformly respond to a given intervention. It is therefore critical to characterize the clinical and preclinical stages of AD subtypes, including the rare autosomal dominant forms caused by known mutations in the PSEN1, APP, and PSEN2 genes that are being studied in the Dominantly Inherited Alzheimer Network study and its associated secondary prevention trial. Similar efforts are occurring in an extended Colombian family with a PSEN1 mutation, in APOE ε4 homozygotes, and in Down syndrome. Despite commonalities in the mechanisms producing the AD phenotype, there are also differences that reflect specific genetic origins. Treatment modalities should be chosen and trials designed with these differences in mind. Ideally, the varying pathological cascades involved in the different subtypes of AD should be defined so that both areas of overlap and of distinct differences can be taken into account. At the very least, clinical trials should determine the influence of known genetic factors in post hoc analyses.
    Current Neurology and Neuroscience Reports 11/2014; 14(11):499. DOI:10.1007/s11910-014-0499-8 · 3.67 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The aqueous decoction of Pterocarpus erinaceus has been traditionally used in Benin against memory troubles. New strategies are needed against Alzheimer's disease (AD), for, to date, AD treatment is symptomatic and consists in drugs treating the cognitive decline. An interesting target is the β-amyloid peptide (Aβ), whose accumulation and progressive deposition into amyloid plaques are key events in AD aetiology. Identifying new and more selective γ-secretase inhibitors or modulators (none of the existing has proven so far to be selective or fully efficient) appears in this respect of particular interest. We studied the activity and mechanisms of action of Pterocarpus erinaceus kino aqueous extract, after the removal of catechic tannins (KAST). We tested KAST at non-toxic concentrations on cells expressing the human Amyloid Precursor Protein (APP695), as well as on primary neurons. P. erinaceus extract was found to inhibit Aβ release in both models. We further showed that KAST inhibited γ-secretase activity in cell-free and in vitro assays, strongly suggesting that KAST is a natural γ-secretase inhibitor. Importantly, this extract did not inhibit the cleavage of Notch, another γ-secretase substrate responsible for major detrimental side effects observed with γ-secretase inhibitors. Epicatechin was further identified in KAST by HPLC-MS. P. erinaceus kino extract appears therefore as a new γ-secretase inhibitor selective towards APP processing. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Journal of Ethnopharmacology 01/2015; 163. DOI:10.1016/j.jep.2015.01.028 · 2.94 Impact Factor
  • Source

Full-text (2 Sources)

Available from
Jun 1, 2014