Peripheral treatment with enoxaparin exacerbates amyloid plaque pathology in Tg2576 mice

J Neurosci Res. 2017 Apr;95(4):992-999. doi: 10.1002/jnr.23880. Epub 2016 Aug 21.


Alzheimer's disease (AD) is a complex, progressive neurological disorder characterized by the formation of extracellular amyloid plaques composed of β-amyloid protein (Aβ), the key component in pathogenesis of AD. Peripheral administration of enoxaparin (ENO) reportedly reduces the level of Aβ 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 Aβ 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 Aβ in Tg2576 mice. Surprisingly, our results indicated that ENO significantly increases the Aβ42/Aβ40 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 Aβ40 and Aβ42 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. © 2016 Wiley Periodicals, Inc.

Keywords: Alzheimer's disease; Aβ; amyloid plaques; amyloid precursor protein transgenic mice; enoxaparin; β-amyloid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM10 Protein / metabolism
  • Alzheimer Disease* / chemically induced
  • Alzheimer Disease* / genetics
  • Alzheimer Disease* / pathology
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Aspartic Acid Endopeptidases / metabolism
  • Brain / drug effects*
  • Brain / metabolism
  • Disease Models, Animal
  • Enoxaparin / toxicity*
  • Female
  • Fibrinolytic Agents / toxicity*
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • Mutation / genetics
  • Plaque, Amyloid / chemically induced*
  • Plaque, Amyloid / genetics
  • Protein Aggregates / drug effects
  • Protein Aggregates / genetics


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Enoxaparin
  • Fibrinolytic Agents
  • Membrane Proteins
  • Protein Aggregates
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, mouse
  • ADAM10 Protein
  • Adam10 protein, mouse