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

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.

• Authors: Dusica Maysinger, Jeff Ji, Alexandre Moquin, Shireen Hossain, Mark A Hancock, Issan Zhang, Philip K Y Chang, Matthew Rigby, Madeleine Anthonisen, Peter Grütter, John Breitner, R Anne McKinney, Sabine Reimann, Rainer Haag, Gerhard Multhaup
• Journal: ACS chemical neuroscience (ACS Chem Neurosci) Vol. 9 Issue 2 Pg. 260-271 (02 21 2018) ISSN: 1948-7193 [Electronic] United States
• PMID: 29078046 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Dendrimers
• Lipocalin-2
• Neuroprotective Agents
• Peptide Fragments
• amyloid beta-protein (1-42)
• enhanced green fluorescent protein
• Green Fluorescent Proteins
• Glycerol

Topics

• Amyloid beta-Peptides (administration & dosage, metabolism, toxicity)
• Animals
• Cells, Cultured
• Cerebral Cortex (drug effects, metabolism, pathology)
• Dendrimers (pharmacology)
• Dendritic Spines (drug effects, metabolism, pathology)
• Glycerol (analogs & derivatives, pharmacology)
• Green Fluorescent Proteins (genetics, metabolism)
• Hippocampus (drug effects, metabolism, pathology)
• Humans
• Lipocalin-2 (metabolism)
• Mice, Inbred C57BL
• Mice, Transgenic
• Microscopy, Atomic Force
• Microscopy, Electron, Transmission
• Microscopy, Fluorescence
• Neuroglia (drug effects, metabolism, pathology)
• Neuroimmunomodulation (drug effects, physiology)
• Neuroprotective Agents (pharmacology)
• Peptide Fragments (administration & dosage, metabolism, toxicity)
• Protein Aggregation, Pathological (drug therapy, metabolism, pathology)
• Surface Plasmon Resonance
• Synapses (drug effects, metabolism, pathology)
• Tissue Culture Techniques