Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members

The amyloid precursor protein (APP) involved in Alzheimer's disease is a me mber of a larger gene family including amyloid precursor-like proteins APLP 1 and APLP2. We generated and examined the phenotypes of mice lacking indiv idual or all possible combinations of APP family members to assess potentia l functional redundancies within the gene family. Mice deficient for the ne rvous system-specific APLP1 protein showed a postnatal growth deficit as th e only obvious abnormality. In contrast to this minor phenotype, APLP2(-/-) /APLP1(-/-) and APLP2(-/-) / APP(-/-) mice proved lethal early postnatally . Surprisingly, APLP1(-/-) /APP(-/-) mice were viable, apparently normal, a nd showed no compensatory upregulation of APLP2 expression. These data indi cate redundancy between APLP2 and both other family members and corroborate a key physiological role for APLP2. This view gains further support by the observation that APLP1(-/-) /APP(-/-) /APLP2(+/-) mice display postnatal l ethality. In addition, they provide genetic evidence for at least some dist inct physiological roles of APP and APLP2 by demonstrating that combination s of single knock-outs with the APLP1 mutation resulted in double mutants o f clearly different phenotypes, being either lethal, or viable. None of the lethal double mutants displayed, however, obvious histopathological abnorm alities in the brain or any other organ examined. Moreover, cortical neuron s from single or combined mutant mice showed unaltered survival rates under basal culture conditions and unaltered susceptibility to glutamate excitot oxicity in vitro.