Peripheral Treatment With Enoxaparin Exacerbates Amyloid Plaque Pathology in Tg2576 Mice

Alzheimer's disease (AD) is a complex, progressive neurological disorder characterized by the formation of extracellular amyloid plaques composed of beta-amyloid protein (A beta), the key component in pathogenesis of AD. Peripheral administration of enoxaparin (ENO) reportedly reduces the level of A beta and the amyloid plaques in the cortex of amyloid precursor protein (APP) transgenic mice. However, the exact mechanism of these effects is unclear. Our previous studies indicated that ENO can inhibit APP processing to A beta in primary cortical cells from Tg2576 mice by downregulating BACE1 levels. This study examines whether ENO-induced reduction of amyloid load is due to the decreased APP processing to A beta in Tg2576 mice. Surprisingly, our results indicated that ENO significantly increases the A beta 42/A beta 40 ratio in cortex and enhances the amyloid plaque load in both cortex and hippocampus, although overall APP processing was not influenced by ENO. Moreover, ENO stimulated the aggregation of both A beta 40 and A beta 42 in vitro. Although ENO has been reported to improve cognition in vivo and has potential as a therapeutic agent for AD, the results from our study suggest that ENO can exacerbate the amyloid pathology, and the strategy of using ENO for the treatment of AD may require further assessment. (C) 2016 Wiley Periodicals, Inc.