The effects of apolipoproteins E3 and E4 on the transforming growth factor-β system in targeted replacement mice.

This study examined the possibility that apolipoprotein E4 (apoE4), the most prevalent genetic risk factor of Alzheimer's disease, interacts isoform specifically with the transforming growth factor (TGF)-β system. This was pursued by measurements of the effects of apoE3 and apoE4 on the levels of TGF-β ligands and on activation of the Smad system in brains of human apoE targeted replacement mice, utilizing Western blot. The study revealed that apoE4 reduces, isoform specifically, the levels of TGF-β(1), TGF-β(2) and TGF-β(3) in the septum and of TGF-β(3) in the hippocampus. In contrast, the levels and extent of phosphorylation of Smad1, 5 and 8 as well as of Smad2 and Smad3 in these brain areas were not affected by apoE4, suggesting that the apoE4-driven effects on the TGF-β system may be mediated via the Smad-independent non-canonical pathway. The possible role of the TGF-β system in mediating the pathological effects of apoE4 is discussed.