APH-1 is a polytopic membrane protein that functions as a component of presenilin-gamma-secretase complexes, Two homologous genes of APH-1 exist in humans, APH-1a and APH-1b, and alternative splicing of the former generates two isoforms, APH-1aS and APH-1aL. We performed semi-quantitative reverse transcription-PCR analysis to investigate mRNA expression of these three APH-1 forms in human cell lines and tissues. We found that both APH-1a and APH-1b were expressed in almost all tissues, and that APH-1aS was 1.5-3 times more abundantly expressed than APH-1aL. We examined the effect of small interfering RNA-mediated knock down of APH-1a or APH-1b on APH-1 mRNA expression and presenilin complex protein expression. We found that knock down of APH-1a, but not APH-1b, resulted in impaired maturation of nicastrin and reduced expression of presenilin 1, presenilin 2, and PEN-2 proteins. These findings indicate that APH-1a plays an essential role in the formation of presenilin-gamma-secretase complexes. (C) 2004 Elsevier Inc. All rights reserved.