Enoxaparin treatment administered at both early and late stages of amyloid β deposition improves cognition of APPswe/PS1dE9 mice with differential effects on brain Aβ levels.

Abstract Enoxaparin (Enox), a low molecular weight heparin, has been shown to lower brain amyloid β (Aβ) load in a mouse model for Alzheimer's disease. However, the effect of Enox on cognition was not studied. Therefore, we examined the effect of peripheral Enox treatment on cognition and brain Aβ levels in the APPswe/PS1dE9 mouse model by giving injections at an early (starting at 5 months of age) and late (starting at 10 and 12 months of age) stage of Aβ accumulation for 3 months. Although Enox had no effect on behaviour in the open field at any age, it improved spatial memory in the Morris water maze in 5-, 10- and 12-month-old mice. Furthermore, Enox treatment seemed to decrease guanidine HCl-extracted brain Aβ levels at 5 months of age, but significantly increased guanidine HCl-extracted Aβ42 and Aβ40 levels in both 10- and 12-month-old mice. In vitro , Enox increased aggregation of Aβ, even when Aβ was pre-aggregated. In conclusion, Enox treatment, either at an early or a late stage of Aβ accumulation, could improve cognition in APPswe/PS1dE9 mice. However, since Enox treatment at an early stage of Aβ accumulation decreased guanidine HCl-extracted Aβ levels and Enox treatment at a late stage enhanced guanidine HCl-extracted Aβ levels, it seems that Enox influences Aβ deposition differently at different stages of Aβ pathology. In any case, our study suggests that enoxaparin treatment has potential as a therapeutic agent for Alzheimer's disease.