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The Journal of Neuroscience, January 5, 2005, 25(1):192-198; doi:10.1523/JNEUROSCI.3814-04.2005
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Neurobiology of Disease
APH-1a Is the Principal Mammalian APH-1 Isoform Present in  -Secretase Complexes during Embryonic Development
Guojun Ma,1
Tong Li,2
Donald L. Price,1,2,3 and
Philip C. Wong1,2
Departments of 1Neuroscience, 2Pathology, and 3Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
APH-1 (anterior pharynx defective) along with nicastrin and PEN-2 (presenilin enhancer) are essential components of the presenilin (PS)-dependent  -secretase complex. There exist three murine Aph-1 alleles termed Aph-1a, Aph-1b, and Aph-1c that encode four distinct APH-1 isoforms: APH-1aL and APH-1aS derived from differential splicing of Aph-1a, APH-1b, and APH-1c. To determine the contributions of mammalian APH-1 homologs in formation of functional -secretase complexes, we generated Aph-1a-/- mice and derived immortalized fibroblasts from these embryos. Compared with littermate controls, the development of Aph-1a-/- embryos was dramatically retarded by embryonic day 9.5 and exhibited patterning defects that resemble, but are not identical to, those of Notch1, nicastrin, or PS null embryos. Moreover, in immortalized Aph-1a-/- fibroblasts, the levels of nicastrin, PS fragments, and PEN-2 were dramatically decreased. Consequently, deletion of Aph-1a resulted in significant reduction in levels of high-molecular-weight -secretase complex and secretion of  -amyloid (A). Importantly, complementation analysis revealed that all mammalian APH-1 isoforms were capable of restoring the levels of nicastrin, PS, and PEN-2, as well as A secretion in Aph-1a-/- cells. Together, our findings establish that APH-1a is the major mammalian APH-1 homolog present in PS-dependent -secretase complexes during embryogenesis and support the view that mammalian APH-1 isoforms define a set of distinct functional -secretase complexes.
Key words: Aph-1a null mice; APH-1 isoforms; -secretase complexes; nicastrin; presenilins; Alzheimer's disease
Received Sep 14, 2004;
revised November 12, 2004;
accepted November 14, 2004.
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J. Biol. Chem.,
June 12, 2009;
284(24):
16298 - 16307.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Serneels, J. Van Biervliet, K. Craessaerts, T. Dejaegere, K. Horre, T. Van Houtvin, H. Esselmann, S. Paul, M. K. Schafer, O. Berezovska, et al.
{gamma}-Secretase Heterogeneity in the Aph1 Subunit: Relevance for Alzheimer's Disease
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May 1, 2009;
324(5927):
639 - 642.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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August 1, 2008;
23(4):
194 - 204.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Dejaegere, L. Serneels, M. K. Schafer, J. Van Biervliet, K. Horre, C. Depboylu, D. Alvarez-Fischer, A. Herreman, M. Willem, C. Haass, et al.
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PNAS,
July 15, 2008;
105(28):
9775 - 9780.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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July 11, 2008;
283(28):
19489 - 19498.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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Epidermal Growth Factor Receptor and Notch Pathways Participate in the Tumor Suppressor Function of {gamma}-Secretase
J. Biol. Chem.,
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282(44):
32264 - 32273.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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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]
|
|
|
|
|
|
|
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
PNAS,
June 19, 2007;
104(25):
10613 - 10618.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Alves da Costa, C. Sunyach, R. Pardossi-Piquard, J. Sevalle, B. Vincent, N. Boyer, T. Kawarai, N. Girardot, P. St. George-Hyslop, and F. Checler
Presenilin-dependent gamma-secretase-mediated control of p53-associated cell death in Alzheimer's disease.
J. Neurosci.,
June 7, 2006;
26(23):
6377 - 6385.
[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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
P. Krawitz, C. Haffner, R. Fluhrer, H. Steiner, B. Schmid, and C. Haass
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J. Biol. Chem.,
November 25, 2005;
280(47):
39515 - 39523.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Mastrangelo, P. M. Mathews, M. A. Chishti, S. D. Schmidt, Y. Gu, J. Yang, M. J. Mazzella, J. Coomaraswamy, P. Horne, B. Strome, et al.
Dissociated phenotypes in presenilin transgenic mice define functionally distinct {gamma}-secretases
PNAS,
June 21, 2005;
102(25):
8972 - 8977.
[Abstract]
[Full Text]
[PDF]
|
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|
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