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The Journal of Neuroscience, April 15, 2003, 23(8):3272
Nicastrin Is Required for Assembly of Presenilin/ -Secretase
Complexes to Mediate Notch Signaling and for Processing and Trafficking
of  -Amyloid Precursor Protein in Mammals
Tong
Li1,
Guojun
Ma1, 2,
Huaibin
Cai1,
Donald L.
Price1, 2, 3, and
Philip C.
Wong1, 2
Departments of 1 Pathology, 2 Neuroscience,
and 3 Neurology, The Johns Hopkins University School of
Medicine, Baltimore, Maryland 21205
Recent studies indicate that nicastrin (NCT) and presenilins
form functional components of a multimeric  -secretase complex required for the regulated intramembraneous proteolysis of Notch and  -amyloid (A) precursor protein (APP). To determine whether nicastrin is required for proteolytic processing of Notch and APP in
mammals and the role of nicastrin in presenilin/-secretase complex
assembly, we generated nicastrin-deficient
(NCT /) mice and derived
fibroblasts from NCT/ embryos.
Nicastrin-null embryos died by embryonic day 10.5 and exhibited several
patterning defects, including abnormal somite segmentation, phenotypes
that are reminiscent of embryos lacking Notch1 or both presenilins.
Importantly, secretion of A peptides is abolished in
NCT/ fibroblasts, whereas it is
reduced by ~50% in NCT+/ cells;
the failure to generate A peptides in
NCT/ cells is accompanied by
destabilization of the presenilin/-secretase complex and
accumulation of APP-C-terminal fragments. Moreover, APP
trafficking analysis in NCT/
fibroblasts revealed a significant delay in the rate of APP
reinternalization compared with that of control cells. Together, these
results establish that nicastrin is an essential component of the
multimeric -secretase complex in mammals required for both
-secretase activity and APP trafficking and suggest that nicastrin
may be a valuable therapeutic target for Alzheimer's disease.
Key words:
nicastrin knock-out mice; nicastrin-deficient
fibroblasts; presenilin/-secretase complex; Notch signaling; APP
processing and trafficking; Alzheimer's disease
Copyright © 2003 Society for Neuroscience 0270-6474/03/2383272-06$05.00/0
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October 9, 2009;
284(41):
27838 - 27847.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Tabuchi, G. Chen, T. C. Sudhof, and J. Shen
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J. Neurosci.,
June 3, 2009;
29(22):
7290 - 7301.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Futai, S. Yagishita, and S. Ishiura
Nicastrin Is Dispensable for {gamma}-Secretase Protease Activity in the Presence of Specific Presenilin Mutations
J. Biol. Chem.,
May 8, 2009;
284(19):
13013 - 13022.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. S. Vetrivel, X. Meckler, Y. Chen, P. D. Nguyen, N. G. Seidah, R. Vassar, P. C. Wong, M. Fukata, M. Z. Kounnas, and G. Thinakaran
Alzheimer Disease A{beta} Production in the Absence of S-Palmitoylation-dependent Targeting of BACE1 to Lipid Rafts
J. Biol. Chem.,
February 6, 2009;
284(6):
3793 - 3803.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Chavez-Gutierrez, A. Tolia, E. Maes, T. Li, P. C. Wong, and B. de Strooper
Glu332 in the Nicastrin Ectodomain Is Essential for {gamma}-Secretase Complex Maturation but Not for Its Activity
J. Biol. Chem.,
July 18, 2008;
283(29):
20096 - 20105.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. S. Vetrivel, X. Zhang, X. Meckler, H. Cheng, S. Lee, P. Gong, K. O. Lopes, Y. Chen, N. Iwata, K.-J. Yin, et al.
Evidence That CD147 Modulation of {beta}-Amyloid (A{beta}) Levels Is Mediated by Extracellular Degradation of Secreted A{beta}
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283(28):
19489 - 19498.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Li, H. Wen, C. Brayton, P. Das, L. A. Smithson, A. Fauq, X. Fan, B. J. Crain, D. L. Price, T. E. Golde, et al.
Epidermal Growth Factor Receptor and Notch Pathways Participate in the Tumor Suppressor Function of {gamma}-Secretase
J. Biol. Chem.,
November 2, 2007;
282(44):
32264 - 32273.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Li, H. Wen, C. Brayton, F. M. Laird, G. Ma, S. Peng, L. Placanica, T. C. Wu, B. J. Crain, D. L. Price, et al.
Moderate Reduction of {gamma}-Secretase Attenuates Amyloid Burden and Limits Mechanism-Based Liabilities
J. Neurosci.,
October 3, 2007;
27(40):
10849 - 10859.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Gridley
Notch signaling in vascular development and physiology
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August 1, 2007;
134(15):
2709 - 2718.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y.-w. Zhang, R. Wang, Q. Liu, H. Zhang, F.-F. Liao, and H. Xu
Presenilin/{gamma}-secretase-dependent processing of beta-amyloid precursor protein regulates EGF receptor expression
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June 19, 2007;
104(25):
10613 - 10618.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Spasic, T. Raemaekers, K. Dillen, I. Declerck, V. Baert, L. Serneels, J. Fullekrug, and W. Annaert
Rer1p competes with APH-1 for binding to nicastrin and regulates {gamma}-secretase complex assembly in the early secretory pathway
J. Cell Biol.,
February 26, 2007;
176(5):
629 - 640.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H.-S. Chang, M. D. Anway, S. S. Rekow, and M. K. Skinner
Transgenerational Epigenetic Imprinting of the Male Germline by Endocrine Disruptor Exposure during Gonadal Sex Determination
Endocrinology,
December 1, 2006;
147(12):
5524 - 5541.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Wang, Y.-w. Zhang, X. Zhang, R. Liu, X. Zhang, S. Hong, K. Xia, J. Xia, Z. Zhang, and H. Xu
Transcriptional regulation of APH-1A and increased {gamma}-secretase cleavage of APP and Notch by HIF-1 and hypoxia
FASEB J,
June 1, 2006;
20(8):
1275 - 1277.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Wang, Y.-w. Zhang, P. Sun, R. Liu, X. Zhang, X. Zhang, K. Xia, J. Xia, H. Xu, and Z. Zhang
Transcriptional Regulation of PEN-2, a Key Component of the {gamma}-Secretase Complex, by CREB
Mol. Cell. Biol.,
February 15, 2006;
26(4):
1347 - 1354.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Miele
Notch Signaling
Clin. Cancer Res.,
February 15, 2006;
12(4):
1074 - 1079.
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Watanabe, T. Tomita, C. Sato, T. Kitamura, Y. Morohashi, and T. Iwatsubo
Pen-2 Is Incorporated into the {gamma}-Secretase Complex through Binding to Transmembrane Domain 4 of Presenilin 1
J. Biol. Chem.,
December 23, 2005;
280(51):
41967 - 41975.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. S. Vetrivel, H. Cheng, S.-H. Kim, Y. Chen, N. Y. Barnes, A. T. Parent, S. S. Sisodia, and G. Thinakaran
Spatial Segregation of {gamma}-Secretase and Substrates in Distinct Membrane Domains
J. Biol. Chem.,
July 8, 2005;
280(27):
25892 - 25900.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y.-w. Zhang, W.-j. Luo, H. Wang, P. Lin, K. S. Vetrivel, F. Liao, F. Li, P. C. Wong, M. G. Farquhar, G. Thinakaran, et al.
Nicastrin Is Critical for Stability and Trafficking but Not Association of Other Presenilin/{gamma}-Secretase Components
J. Biol. Chem.,
April 29, 2005;
280(17):
17020 - 17026.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Xie and Q. Guo
PAR-4 Is Involved in Regulation of {beta}-Secretase Cleavage of the Alzheimer Amyloid Precursor Protein
J. Biol. Chem.,
April 8, 2005;
280(14):
13824 - 13832.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Serneels, T. Dejaegere, K. Craessaerts, K. Horre, E. Jorissen, T. Tousseyn, S. Hebert, M. Coolen, G. Martens, A. Zwijsen, et al.
Differential contribution of the three Aph1 genes to {gamma}-secretase activity in vivo
PNAS,
February 1, 2005;
102(5):
1719 - 1724.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Ma, T. Li, D. L. Price, and P. C. Wong
APH-1a Is the Principal Mammalian APH-1 Isoform Present in {gamma}-Secretase Complexes during Embryonic Development
J. Neurosci.,
January 5, 2005;
25(1):
192 - 198.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. S. Vetrivel, H. Cheng, W. Lin, T. Sakurai, T. Li, N. Nukina, P. C. Wong, H. Xu, and G. Thinakaran
Association of {gamma}-Secretase with Lipid Rafts in Post-Golgi and Endosome Membranes
J. Biol. Chem.,
October 22, 2004;
279(43):
44945 - 44954.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Shirotani, D. Edbauer, S. Prokop, C. Haass, and H. Steiner
Identification of Distinct {gamma}-Secretase Complexes with Different APH-1 Variants
J. Biol. Chem.,
October 1, 2004;
279(40):
41340 - 41345.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Prokop, K. Shirotani, D. Edbauer, C. Haass, and H. Steiner
Requirement of PEN-2 for Stabilization of the Presenilin N-/C-terminal Fragment Heterodimer within the {gamma}-Secretase Complex
J. Biol. Chem.,
May 28, 2004;
279(22):
23255 - 23261.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X.-X. Yan, T. Li, C. M. Rominger, S. R. Prakash, P. C. Wong, R. E. Olson, R. Zaczek, and Y.-W. Li
Binding Sites of {gamma}-Secretase Inhibitors in Rodent Brain: Distribution, Postnatal Development, and Effect of Deafferentation
J. Neurosci.,
March 24, 2004;
24(12):
2942 - 2952.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. R. Fortna, A. S. Crystal, V. A. Morais, D. S. Pijak, V. M.-Y. Lee, and R. W. Doms
Membrane Topology and Nicastrin-enhanced Endoproteolysis of APH-1, a Component of the {gamma}-Secretase Complex
J. Biol. Chem.,
January 30, 2004;
279(5):
3685 - 3693.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Aguzzi and C. Haass
Games Played by Rogue Proteins in Prion Disorders and Alzheimer's Disease
Science,
October 31, 2003;
302(5646):
814 - 818.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. A. Morais, A. S. Crystal, D. S. Pijak, D. Carlin, J. Costa, V. M.-Y. Lee, and R. W. Doms
The Transmembrane Domain Region of Nicastrin Mediates Direct Interactions with APH-1 and the {gamma}-Secretase Complex
J. Biol. Chem.,
October 31, 2003;
278(44):
43284 - 43291.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S.-H. Kim, T. Ikeuchi, C. Yu, and S. S. Sisodia
Regulated Hyperaccumulation of Presenilin-1 and the "{gamma}-Secretase" Complex: EVIDENCE FOR DIFFERENTIAL INTRAMEMBRANOUS PROCESSING OF TRANSMEMBRANE SUBSTRATES
J. Biol. Chem.,
September 5, 2003;
278(36):
33992 - 34002.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Li, G. J. Fici, C.-A. Mao, R. L. Myers, R. Shuang, G. P. Donoho, A. M. Pauley, C. S. Himes, W. Qin, I. Kola, et al.
Positive and Negative Regulation of the {gamma}-Secretase Activity by Nicastrin in a Murine Model
J. Biol. Chem.,
August 29, 2003;
278(35):
33445 - 33449.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
