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TitleDendritic Polyglycerol Sulfates in the Prevention of Synaptic Loss and Mechanism of Action on Glia.
Publication TypeJournal Article
Year of Publication2018
AuthorsMaysinger, Dusica, Jeff Ji, Alexandre Moquin, Shireen Hossain, Mark A. Hancock, Issan Zhang, Philip K Y Chang, Matthew Rigby, Madeleine Anthonisen, Peter Grutter, John Breitner, Anne R McKinney, Sabine Reimann, Rainer Haag, and Gerhard Multhaup
JournalACS Chem Neurosci
Volume9
Issue2
Pagination260-271
Date Published2018 02 21
ISSN1948-7193
KeywordsAmyloid beta-Peptides, Animals, Cells, Cultured, Cerebral Cortex, Dendrimers, Dendritic Spines, Glycerol, Green Fluorescent Proteins, Hippocampus, Humans, Lipocalin-2, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Atomic Force, Microscopy, Electron, Transmission, Microscopy, Fluorescence, Neuroglia, Neuroimmunomodulation, Neuroprotective Agents, Peptide Fragments, Protein Aggregation, Pathological, Surface Plasmon Resonance, Synapses, Tissue Culture Techniques
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 (Aβ) 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 Aβ 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 Aβ, i.e., a direct interaction between dPGS and Aβ 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.

DOI10.1021/acschemneuro.7b00301
Alternate JournalACS Chem Neurosci
PubMed ID29078046
Grant ListMOP-119425 / / CIHR / Canada
MOP-133411 / / CIHR / Canada