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.
Enoxaparin (Enox), a low molecular weight heparin, has been shown to lower brain amyloid beta (A beta) 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 A beta 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 A beta 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 A beta levels at 5 months of age, but significantly increased guanidine HCl-extracted A beta 42 and A beta 40 levels in both 10- and 12-month-old mice. In vitro, Enox increased aggregation of A beta, even when A beta was pre-aggregated. In conclusion, Enox treatment, either at an early or a late stage of A beta accumulation, could improve cognition in APPswe/PS1dE9 mice. However, since Enox treatment at an early stage of A beta accumulation decreased guanidine HCl-extracted A beta levels and Enox treatment at a late stage enhanced guanidine HCl-extracted A beta levels, it seems that Enox influences A beta deposition differently at different stages of A beta pathology. In any case, our study suggests that enoxaparin treatment has potential as a therapeutic agent for Alzheimer's disease.
Timmer
Nienke M
NM
Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Alzheimer Centre Nijmegen, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. n.timmer@neuro.umcn.nl
van Dijk
Laura
L
van der Zee
Catharina E E M
CE
Kiliaan
Amanda
A
de Waal
Robert M W
RM
Verbeek
Marcel M
MM
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism*; D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D017984:Enoxaparin / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000188:drug therapy* / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D017984:Enoxaparin