GENERATION OF APLP2 KO MICE AND EARLY POSTNATAL LETHALITY IN APLP2 APP DOUBLE KO MICE/

Amyloid precursor protein (APP) is a member of a larger gene family in cluding amyloid precursor-like proteins (APLP), APLP2 and APLP1. To ex amine the function of APLP2 in vivo, we generated APLP2 knockout (KO) mice. They are of normal size, fertile, and appear healthy up to 22 mo nths of age. We observed no impaired axonal outgrowth of olfactory sen sory neurons following bulbectomy, suggesting against an important rol e for APLP2 alone in this process. Because APLP2 and APP are highly ho mologous and may serve similar functions in vivo, we generated mice wi th targeted APLP2 and APP alleles. Approximately 80% of double KO mice die within the first week after birth, suggesting that APLP2 and APP are required for early postnatal development. The surviving similar to 20% of double KO mice are 20-30% reduced in weight and show difficult y in righting, ataxia, spinning behavior, and a head tilt, suggesting a deficit in balance and/or strength. Adult double KO mice mate poorly , despite apparent normal ovarian and testicular development. Otherwis e, double KO mice appear healthy up to 13 months of age. We conclude, that APLP2 and APP can substitute for each other functionally. (C) 199 7 Elsevier Science Inc.