Elucidation of the principal mechanism for dementia and identification of anti-dementia genes through the analysis of ApoE4 neurotoxicity

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In this study, we were able to establish the neuronal death system induced by ApoE4. With the system, we investigated the molecular mechanism of neuronal death by ApoE4 and we found that (1) neuronal death by ApoE4 was mediated by the LDL receptor-related protein, LRP;(2) LRP-binding protein, RAP, suppressed ApoE4-induced neuronal death; (3) one of other ligands, α2 macroglobulin, suppressed neuronal death; (4)low concentrations of ApoE3 supressed neuronal death caused by ApoE4 (5) neuronal death was suppressed by PTX and the signal was transduced through either Gi1, Gi2, Gi3, or all of them upon binding of ApoE4 to LRP. Since it has been remained controversial whether ApoE4 exerts neurotoxicity, it has to be addressed. For the studies by other groups where ApoE4 did not exert neurotoxicity, we have pointed out that the suppressed toxicity was possibly observed under the different experimental condition or the different cellular condition such as cell kind, expression level of LRP and RAP, and serum treatment in the culture medium. If serum or N2 supplement was added into the culture medium, it caused the results of ApoE4 to not exert neurotoxicity.Instability of α2 macroglobulin (α2M) as well as e4 genotype of apolipoprotein, apoE4 has been pointed out to be the possible risk factor for Alzheimer's disease. Our finding mentioned in (3) provides the first cellular biological evidence for the risk factor. As in (4) above, LRP performs the cellular function of either survival or death depending on it's ligand or the lignad concentration.We will investigate the coupling mechanism of LRP with Gi and the downstream target molecule of Gi. It will be intriguing to study AD by mating the ApoE knock-out mice or human ApoE4 knock-in mice with our AD model mice in the near future.