Session Title: Apolipoprotein-E
APOLIPOPROTEIN E GENOTYPE MODULATES AMYLOID PRECURSOR PROTEIN METABOLISM AND CELL CYCLE REGULATION
P. Huebbe, G. Rimbach
Apolipoprotein E4 (apoE4) genotype is associated with an increased risk for Alzheimer´s disease (AD). This is thought to be in part attributable to an impact of apoE genotype on the processing of the transmembrane amyloid precursor protein (APP) thereby contributing to amyloid beta peptide formation in apoE4 carriers, which is a primary patho-physiological feature of AD. In the present study we determined the effect of apoE genotype on APP metabolism and cell cycle regulation in response to apoE genotype in targeted gene replacement mice. Non-amyloidogenic alpha-secretase mRNA concentration and activity were significantly higher in brains of apoE3 relative to apoE4 mice, while amyloidogenic beta-secretase and gamma-secretase remained unchanged. Relative mRNA concentration of cell cycle related proteins (including cyclin D) was significantly different between apoE3 and apoE4 mice. Overall current data suggest apoE genotype-dependent signalling effects on alpha-secretase activity and cell cycle regulation in the brain.