The presenilins and nicastrin, a type 1 transmembrane glycoprotein, form high molecular weight complexes that are involved in cleaving the beta-amyloid precursor protein (betaAPP) and Notch in their transmembrane domains. The former process (termed gamma-secretase cleavage) generates amyloid beta-peptide (Abeta), which is involved in the pathogenesis of Alzheimer's disease. The latter process (termed S3-site cleavage) generates Notch intracellular domain (NICD), which is involved in intercellular signalling. Nicastrin binds both full-length betaAPP and the substrates of gamma-secretase (C99- and C83-betaAPP fragments), and modulates the activity of gamma-secretase. Although absence of the Caenorhabditis elegans nicastrin homologue (aph-2) is known to cause an embryonic-lethal glp-1 phenotype, the role of nicastrin in this process has not been explored. Here we report that nicastrin binds to membrane-tethered forms of Notch (substrates for S3-site cleavage of Notch), and that, although mutations in the conserved 312-369 domain of nicastrin strongly modulate gamma-secretase, they only weakly modulate the S3-site cleavage of Notch. Thus, nicastrin has a similar role in processing Notch and betaAPP, but the 312-369 domain may have differential effects on these activities. In addition, we report that the Notch and betaAPP pathways do not significantly compete with each other.
"Of the remaining three partners, PEN-2 is crucial for the endoproteolysis of full length PS into PS-NTF and PS-CTF (Ahn et al., 2010; Prokop et al., 2004), while NCT and APH-1 are thought to be important for PS stabilization and trafficking (LaVoie et al., 2003; Zhang et al., 2005). In addition, it has been proposed that NCT participates in the recruitment of Notch1 and APP substrates to γsecretase (Chen et al., 2001; Dries et al., 2009) but this function has been challenged (Chavez-Gutierrez et al., 2008; Futai et al., 2009; Shirotani et al., 2004a; Zhao et al., 2010) and recent reports indicate that APH-1 may play that role (Chen et al., 2010). APH-1 has also been proposed to participate in the catalytic functions of γ-secretase via its conserved histidine residues in TM sequences 5 and 6 (Pardossi-Piquard et al., 2009b; Pei et al., 2011; Serneels et al., 2009). "
[Show abstract][Hide abstract] ABSTRACT: Presenilins (PSs) are catalytic components of the γ-secretase proteolytic complexes that produce Aβ and cell signaling peptides. γ-Secretase substrates are mostly membrane-bound peptides derived following proteolytic cleavage of the extracellular domain of type I transmembrane proteins. Recent work reveals that γ-secretase substrate processing is regulated by proteins termed γ-secretase substrate recruiting factors (γSSRFs) that bridge substrates to γ-secretase complexes. These factors constitute novel targets for pharmacological control of specific γ-secretase products, such as Aβ and signaling peptides. PS familial Alzheimer's disease (FAD) mutants cause a loss of γ-secretase cleavage function at epsilon sites of substrates thus inhibiting production of cell signaling peptides while promoting accumulation of uncleaved toxic substrates. Importantly, γ-secretase inhibitors may cause toxicity in vivo by similar mechanisms. Here we review novel mechanisms that control γ-secretase substrate selection and cleavage and examine their relevance to AD.
Progress in Neurobiology 05/2012; 98(2):166-75. DOI:10.1016/j.pneurobio.2012.05.006 · 9.99 Impact Factor
"Although it has not retained its peptidase activity (Fagan et al., 2001; Fergani et al., 2001), this domain has retained its ability for substrate recognition (Shah et al., 2005). Point mutations within the DAP domain appear to augment amyloid precursor protein (APP) processing, whereas deletions disrupt APP processing , probably by preventing the exit of NCSTN from the endoplasmic reticulum (ER) (Chen et al., 2001; Yu et al., 2000). Given that previous genetic studies have been inconclusive as to the role of NCSTN in AD susceptibility, we have developed a novel functional genomics approach based on the expression of different haplotypes. "
[Show abstract][Hide abstract] ABSTRACT: Nicastrin (NCSTN) is a component of the γ-secretase complex and therefore potentially a candidate risk gene for Alzheimer's disease. Here, we have developed a novel functional genomics methodology to express common locus haplotypes to assess functional differences. DNA recombination was used to engineer 5 bacterial artificial chromosomes (BACs) to each express a different haplotype of the NCSTN locus. Each NCSTN-BAC was delivered to knockout nicastrin (Ncstn(-/-)) cells and clonal NCSTN-BAC(+)/Ncstn(-/-) cell lines were created for functional analyses. We showed that all NCSTN-BAC haplotypes expressed nicastrin protein and rescued γ-secretase activity and amyloid beta (Aβ) production in NCSTN-BAC(+)/Ncstn(-/-) lines. We then showed that genetic variation at the NCSTN locus affected alternative splicing in human postmortem brain tissue. However, there was no robust functional difference between clonal cell lines rescued by each of the 5 different haplotypes. Finally, there was no statistically significant association of NCSTN with disease risk in the 4 cohorts. We therefore conclude that it is unlikely that common variation at the NCSTN locus is a risk factor for Alzheimer's disease.
Neurobiology of aging 03/2012; 33(8):1848.e1-13. DOI:10.1016/j.neurobiolaging.2012.02.005 · 5.01 Impact Factor
"The γ-secretase complex contains four components, presenilin 1 (PS1), nicastrin, anterior pharynx defective-1 (APH-1) and presenilin enhancer-2 (PEN-2).5 Two aspartate residues located at the transmembrane domain 6 and 7 of PS1 constitute the active site of the γ-secretase.6 Nicastrin was found to associate with the C-terminal fragments of APP and required for γ-secretase activity.7,8 Genetic screens in Caenorhabditis elegans revealed two additional components of the γ-secretase components, APH-1,9 and PEN-2.10 "
[Show abstract][Hide abstract] ABSTRACT: The development of amyloid-containing neuritic plaques is an invariable characteristic of Alzheimer's diseases (AD). The conversion from monomeric amyloid β protein (Aβ) to oligomeric Aβ and finally neuritic plaques is highly dynamic. The specific Aβ species that is correlated with disease severity remains to be discovered. Oligomeric Aβ has been detected in cultured cells, rodent and human brains, as well as human cerebrospinal fluid. Synthetic, cell, and brain derived Aβ oligomers have been found to inhibit hippocampal long-term potentiation (LTP) and this effect can be suppressed by the blockage of Aβ oligomer formation. A large body of evidence suggests that Aβ oligomers inhibit N-methyl-D-aspartate receptor dependent LTP; additional receptors have also been found to elicit downstream pathways upon binding to Aβ oligomers. Amyloid antibodies and small molecular compounds that reduce brain Aβ levels and block Aβ oligomer formation are capable of reversing synaptic dysfunction and these approaches hold a promising therapeutic potential to rescue memory disruption.
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