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Alleles at the Nicastrin locus modify presenilin 1- deficiency phenotype

Rozmahel, Richard; Mount, Howard T J; Chen, Fusheng; Nguyen, Van; Huang, Jean; Erdebil, Serap; Liauw, Jennifer; Yu, Gang; Hasegawa, Hiroshe; Gu, YongJun; Song, You-Qiang; Schmidt, Stephen D; Nixon, Ralph A; Mathews, Paul M; Bergeron, Catherine; Fraser, Paul; Westaway, David; St George-Hyslop, Peter
Presenilin 1 (PS1), presenilin 2, and nicastrin form high molecular weight complexes that are necessary for the endoproteolysis of several type 1 transmembrane proteins, including amyloid precursor protein (APP) and the Notch receptor, by apparently similar mechanisms. The cleavage of the Notch receptor at the 'S3-site' releases a C-terminal cytoplasmic fragment (Notch intracellular domain) that acts as the intracellular transduction molecule for Notch activation. Missense mutations in the presenilins cause familial Alzheimer's disease by augmenting the 'gamma-secretase' cleavage of APP and overproducing one of the proteolytic derivatives, the Abeta peptide. Null mutations in PS1 inhibit both gamma-secretase cleavage of APP and S3-site cleavage of the Notch receptor. Mice lacking PS1 function have defective Notch signaling and die perinatally with severe skeletal and brain deformities. We report here that a genetic modifier on mouse distal chromosome 1, coinciding with the locus containing Nicastrin, influences presenilin-mediated Notch S3-site cleavage and the resultant Notch phenotype without affecting presenilin-mediated APP gamma-site cleavage. Two missense substitutions of residues conserved among vertebrates have been identified in nicastrin. These results indicate that Notch S3-site cleavage and APP gamma-site cleavage are distinct presenilin-dependent processes and support a functional interaction between nicastrin and presenilins in vertebrates. The dissociation of Notch S3-site and APP gamma-site cleavage activities will facilitate development of gamma-secretase inhibitors for treatment of Alzheimer's disease
PMCID:137904
PMID: 12388777
ISSN: 0027-8424
CID: 32537

Calpain Activity Regulates the Cell Surface Distribution of Amyloid Precursor Protein. INHIBITION OF CALPAINS ENHANCES ENDOSOMAL GENERATION OF beta -CLEAVED C-TERMINAL APP FRAGMENTS

Mathews, Paul M; Jiang, Ying; Schmidt, Stephen D; Grbovic, Olivera M; Mercken, Marc; Nixon, Ralph A
In murine L cells, treatment with calpeptin or calpain inhibitor III increased Abeta42, but not Abeta40, secretion in a dose-dependent fashion. This correlated with an increase in the levels of amyloid precursor protein (APP) carboxyl-terminal fragments (CTFs). Immunoprecipitation with novel mAbs directed against the carboxyl-terminus of APP or specific for the beta-cleaved CTF showed that generation of both alpha- and beta-cleaved CTFs increase proportionately following inhibition of calpains. Pulse-chase metabolic labeling confirmed that inhibiting calpains increases the production of alpha- and beta-cleaved APP metabolites. Immunolabeling showed greater betaCTF signal in calpeptin-treated cells, primarily in small vesicular compartments that were shown to be predominantly endosomal by colocalization with early endosomal antigen 1. A second mAb, which recognizes an extracellular/luminal epitope found on both APP and betaCTFs, gave more cell surface labeling of calpeptin-treated cells than control cells. Quantitative binding of this antibody confirmed that inhibiting calpains caused a partial redistribution of APP to the cell surface. These results demonstrate that 1) calpain inhibition results in a partial redistribution of APP to the cell surface, 2) this redistribution leads to an increase in both alpha- and beta-cleavage without changing the ratio of alphaCTFs/betaCTFs, and 3) the bulk of the betaCTFs in the cell are within early endosomes, confirming the importance of this compartment in APP processing
PMID: 12087104
ISSN: 0021-9258
CID: 32534

Mature glycosylation and trafficking of nicastrin modulate its binding to presenilins

Yang, Dun-Sheng; Tandon, Anurag; Chen, Fusheng; Yu, Gang; Yu, Haung; Arawaka, Shigeki; Hasegawa, Hiroshi; Duthie, Monika; Schmidt, Stephen D; Ramabhadran, Triprayer V; Nixon, Ralph A; Mathews, Paul M; Gandy, Samuel E; Mount, Howard T J; St George-Hyslop, Peter; Fraser, Paul E
Nicastrin is an integral component of the high molecular weight presenilin complexes that control proteolytic processing of the amyloid precursor protein and Notch. We report here that nicastrin is most probably a type 1 transmembrane glycoprotein that is expressed at moderate levels in the brain and in cultured neurons. Immunofluorescence studies demonstrate that nicastrin is localized in the endoplasmic reticulum, Golgi, and a discrete population of vesicles. Glycosidase analyses reveal that endogenous nicastrin undergoes a conventional, trafficking-dependent maturation process. However, when highly expressed in transfected cells, there is a disproportionate accumulation of the endo-beta-N-acetylglucosaminidase H-sensitive, immature form, with no significant increase in the levels of the fully mature species. Immunoprecipitation revealed that presenilin-1 interacts preferentially with mature nicastrin, suggesting that correct trafficking and co-localization of the presenilin complex components are essential for activity. These findings demonstrate that trafficking and post-translational modifications of nicastrin are tightly regulated processes that accompany the assembly of the active presenilin complexes that execute gamma-secretase cleavage. These results also underscore the caveat that simple overexpression of nicastrin in transfected cells may result in the accumulation of large amounts of the immature protein, which is apparently unable to assemble into the active complexes capable of processing amyloid precursor protein and Notch
PMID: 12032140
ISSN: 0021-9258
CID: 62376

Autophagic cell death: Relevance to Alzheimer disease neurodegeneration [Meeting Abstract]

Nixon, RA; Mathews, PM; Ginsberg, SD; Duff, K; Mohan, P; Cataldo, AM; Wegiel, J; Yu, WH; Schmidt, SD; Jacobsen, SP; Peterhoff, CM; Terio, N; Keller, JN; Hassinger, L
ISI:000177465301499
ISSN: 0197-4580
CID: 32429

Murine A beta co-deposition in transgenic mice: Analyses with species-specific antibodies and comparison of human and murine A beta 42 : A beta 40 ratios [Meeting Abstract]

Schmidt, S; Jiang, Y; Duff, KEK; Nixon, RA; Mathews, PM; Herzig, MC; Jucker, M; Chishti, MA; Westaway, D; Mercken, M; Staufenbiel, M
ISI:000177465300901
ISSN: 0197-4580
CID: 32422

Autophagy-dependent generation of the amyloid-beta (A beta) peptide [Meeting Abstract]

Yu, WH; Schmidt, SD; Jiang, Y; Mathews, PM; Nixon, RA; Hassinger, L; Cataldo, A
ISI:000177465300050
ISSN: 0197-4580
CID: 32404

Altered APP trafficking and a role for the early endosome in increased beta CTF generation following calpain inhibition [Meeting Abstract]

Mathews, PM; Nixon, RA; Jiang, Y; Schmidt, SD; Grbovic, OM; Mercken, M; Cataldo, AM
ISI:000177465300656
ISSN: 0197-4580
CID: 32414

Quantitation of beta-cleaved carboxy-terminal fragments of APP with a novel ELISA [Meeting Abstract]

Jiang, Y; Schmidt, SD; Mercken, M; Mathews, PM; Nixon, RA
ISI:000177465300064
ISSN: 0197-4580
CID: 32406

Rab5 overexpression in a cell model of AD-related endocytic abnormalities influences processing of beta APP [Meeting Abstract]

Grbovic, OM; Schmidt, SD; Mathews, PM; Nixon, RA; Cataldo, AM
ISI:000177465300052
ISSN: 0197-4580
CID: 32405

AUTOPHAGY IN ALZHEIMER'S DISEASE: AUTOPHAGY - DEPENDENT GENERATION OF THE AMYLOID beta ( Abeta ) PEPTIDE [Meeting Abstract]

Nixon, R. A.; Yu, W. H.; Cataldo, A. M.; Mathews, P. M.; Wegiel, J.; Schmidt, S. D.; Ginsberg, S. D.; Peterhoff, C. M.; Terio, N.; Mohan, P.; Hassinger, L.; Kumar, A.; Lamb, B.
BIOSIS:PREV200300315424
ISSN: 1558-3635
CID: 458992