Dendritic Polyglycerol Sulfates in the Prevention of Synaptic Loss and Mechanism of Action on Glia

Dusica Maysinger, Jeff Ji, Alexandre Moquin, Shireen Hossain, Mark A. Hancock, Issan Zhang, Philip K.Y. Chang, Matthew Rigby, Madeleine Anthonisen, Peter Grütter, John C.S. Breitner, R. Anne McKinney, Sabine Reimann, Rainer Haag, Gerhard Multhaup

Research output: Contribution to journalArticle

Abstract

Dendritic polyglycerols (dPG), particularly dendritic polyglycerol sulfates (dPGS), have been intensively studied due to their intrinsic anti-inflammatory activity. As related to brain pathologies involving neuroinflammation, the current study examined if dPG and dPGS can (i) regulate neuroglial activation, and (ii) normalize the morphology and function of excitatory postsynaptic dendritic spines adversely affected by the neurotoxic 42 amino acid amyloid-β (Aβ42) peptide of Alzheimer disease (AD). The exact role of neuroglia, such as microglia and astrocytes, remains controversial especially their positive and negative impact on inflammatory processes in AD. To test dPGS effectiveness in AD models we used primary neuroglia and organotypic hippocampal slice cultures exposed to Aβ42 peptide. Overall, our data indicate that dPGS is taken up by both microglia and astrocytes in a concentration- and time-dependent manner. The mechanism of action of dPGS involves binding to Aβ42, i.e., a direct interaction between dPGS and Aβ42 species interfered with Aβ fibril formation and reduced the production of the neuroinflammagen lipocalin-2 (LCN2) mainly in astrocytes. Moreover, dPGS normalized the impairment of neuroglia and prevented the loss of dendritic spines at excitatory synapses in the hippocampus. In summary, dPGS has desirable therapeutic properties that may help reduce amyloid-induced neuroinflammation and neurotoxicity in AD.

Original languageEnglish (US)
Pages (from-to)260-271
Number of pages12
JournalACS Chemical Neuroscience
Volume9
Issue number2
DOIs
StatePublished - Feb 21 2018
Externally publishedYes

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Keywords

  • amyloid beta
  • astrocytes
  • Dendritic polyglycerol sulfates
  • dendritic spines
  • LCN-2
  • microglia

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

Cite this

Maysinger, D., Ji, J., Moquin, A., Hossain, S., Hancock, M. A., Zhang, I., Chang, P. K. Y., Rigby, M., Anthonisen, M., Grütter, P., Breitner, J. C. S., McKinney, R. A., Reimann, S., Haag, R., & Multhaup, G. (2018). Dendritic Polyglycerol Sulfates in the Prevention of Synaptic Loss and Mechanism of Action on Glia. ACS Chemical Neuroscience, 9(2), 260-271. https://doi.org/10.1021/acschemneuro.7b00301