Reduced Aph‐1b expression causes tissue‐ and substrate‐specific changes in γ‐secretase activity in rats with a complex phenotype

The γ‐secretase enzyme complex displays intramembrane catalytic activity toward many type I transmembrane proteins, including the Alzheimer‐linked amyloid‐β precursor protein (APP) and the neuregulin receptor ErbB4. Active γ‐secretase is a tetrameric protein complex consisting of presenilin‐1 (or ‐2), nicastrin, PEN‐2, and Aph‐1a (or ‐1b). We have recently discovered that pharmacogenetically bred apomorphine‐susceptible Wistar rats (APO‐SUS) have only one or two copies of the Aph‐1b gene (termed I/I and II/II rats, respectively), whereas their phenotypic counterparts (APO‐UNSUS) have three copies (III/III). As a result, APO‐SUS rats display reduced Aph‐1b expression and a complex phenotype reminiscent of neurodevelopmental disorders. Here we determined in the I/I and III/III rats the γ‐secretase cleavage activity toward the three APP superfamily members, p75 neurotrophin receptor, ErbB4, and neuregulin‐2, and found that the cleavage of only a subset of the substrates was changed. Furthermore, the observed differences were restricted to tissues that normally express relatively high Aph‐1b compared with Aph‐1a levels. Thus, we provide in vivo evidence that subtle alterations in γsecretase subunit composition may lead to a variety of affected (neuro)developmental signaling pathways and, consequently, a complex phenotype.