TY - JOUR
T1 - APH-1a is the principal mammalian APH-1 isoform present in γ-secretase complexes during embryonic development
AU - Ma, Guojun
AU - Li, Tong
AU - Price, Donald L.
AU - Wong, Philip C.
PY - 2005/1/5
Y1 - 2005/1/5
N2 - APH-1 (anterior pharynx defective) along with nicastrin and PEN-2 (presenilin enhancer) are essential components of the presenilin (PS)-dependent γ-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 γ-secretase complexes, we generated Aph-1a-/- mice and derived immortalized fibroblasts from these embryos. Compared with littermate controls, the development 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 γ-secretase complex and secretion of β-amyloid (Aβ). 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 Aβ secretion in Aph-1a-/- cells. Together, our findings establish that APH-1a is the major mammalian APH-1 homolog present in PS-dependent γ-secretase complexes during embryogenesis and support the view that mammalian APH-1 isoforms define a set of distinct functional γ-secretase complexes.
AB - APH-1 (anterior pharynx defective) along with nicastrin and PEN-2 (presenilin enhancer) are essential components of the presenilin (PS)-dependent γ-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 γ-secretase complexes, we generated Aph-1a-/- mice and derived immortalized fibroblasts from these embryos. Compared with littermate controls, the development 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 γ-secretase complex and secretion of β-amyloid (Aβ). 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 Aβ secretion in Aph-1a-/- cells. Together, our findings establish that APH-1a is the major mammalian APH-1 homolog present in PS-dependent γ-secretase complexes during embryogenesis and support the view that mammalian APH-1 isoforms define a set of distinct functional γ-secretase complexes.
KW - APH-1 isoforms
KW - Alzheimer's disease
KW - Aph-1a null mice
KW - Nicastrin
KW - Presenilins
KW - γ-secretase complexes
UR - http://www.scopus.com/inward/record.url?scp=12144250683&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=12144250683&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.3814-04.2005
DO - 10.1523/JNEUROSCI.3814-04.2005
M3 - Article
C2 - 15634781
AN - SCOPUS:12144250683
SN - 0270-6474
VL - 25
SP - 192
EP - 198
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 1
ER -