Safety and pharmacokinetics of CHF5074, a novel gamma-secretase modulator, after multiple oral administrations to healthy humans

tor for Alzheimer disease. A single copy of this variant leads to a 3 fold increased risk compared with the most common APOE E3 allele whereas inheritance of the rare APOE E2 reduces this risk by about half. However, despite the discovery of these strong genetic clues, the mechanism whereby apoE confers risk remains uncertain. Methods: In order to decipher how the different ApoE isoforms (ApoEE2, -E3 and -E4) impact the formation and stability of amyloid plaques, AAV4 vectors coding for each ApoE isoform were injected into the ventricle of 7 month-old APP/PS mice. Using in vivo multiphoton imaging, we tracked populations of amyloid deposits at baseline and after exposure to ApoE over a two-month interval, thus allowing us to have a dynamic view of amyloidosis progression in a living animal. Results: We observed that the kinetic of amyloid deposits progression varies according to each isoform, so that ApoE4 injected mice have a 36% increase of senile plaques (p < 0.05) whereas mice treated with ApoE2 present a 25% decrease of the number of amyloid deposits (p < 0.05) compared to ApoE3 after 2 months. The post-mortem analysis revealed the presence of human ApoE proteins in the epithelial lining of the ventricle but it also decorates plaques in the cortex, reflecting a large diffusion of the protein and its accumulation where Aß peptides are deposited. In some of the injected mice, the amount of ApoE protein detected by ELISA reached the level of ApoE measured in transgenic animals, confirming that this approach may be efficient to increase the global content of a secreted protein throughout the entire brain. Conclusions: Overall, our results suggest that a single injection of an AAV4 vector into the ventricle leads to a diffuse and sustained overexpression of the different ApoE isoforms in the mouse brain. Moreover, the ApoE4 overexpression accelerates the progression of amyloid deposition whereas ApoE2 alleviates the course of the disease. These results demonstrated that manipulation of the ApoE status in the brain may be an interesting approach to modulate amyloidosis.