Secretion of the amyloid precursor protein is elevated isoform specifically by apolipoprotein E4

Genetic studies suggest that the neuropathology and etiology of Alzheimer's disease (AD) are associated with several genotypes including mutations in the amyloid precursor protein (APP) gene and the allele E4 of apolipoprotein E (apoE). The present study investigated the possibility that cross talk interactions exist between APP and apoE and the extent to which they are affected by the apoE genotype. This was pursued by cell culture and immunoblot experiments utilizing neuroblastoma N2a cells in which the effects of distinct apoE isoforms on the levels of intracellular APP and of secreted APPs were determined. This revealed that treatment of the cells with apoE4, the AD risk factor, resulted in a marked increase in the levels of secreted APPs. This effect was dose dependent (ED50 approximately/= 2.5 microg/ml) and isoform specific in that apoE3 had virtually no effect on the secretion of APPs.