APH-1a is the principal mammalian APH-1 isoform present in γ-secretase complexes during embryonic development

Guojun Ma, Tong Li, Donald L. Price, Philip C. Wong

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)192-198
Number of pages7
JournalJournal of Neuroscience
Volume25
Issue number1
DOIs
StatePublished - Jan 5 2005

Keywords

  • APH-1 isoforms
  • Alzheimer's disease
  • Aph-1a null mice
  • Nicastrin
  • Presenilins
  • γ-secretase complexes

ASJC Scopus subject areas

  • Neuroscience(all)

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