Dendritic Polyglycerol Sulfate Inhibits Microglial Activation and Reduces Hippocampal CA1 Dendritic Spine Morphology Deficits

Maysinger, Dušica; Gröger, Dominic; Lake, Andrew C.; Licha, Kai; Weinhart, Marie; Chang, Philip K.-Y.; Mulvey, Rose; Haag, Rainer; McKinney, R. Anne

doi:10.1021/acs.biomac.5b00999

Cited by 42 publications

(54 citation statements)

References 65 publications

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“…Twenty-five distinct mouse lines were produced, each with subtly different patterns of expression (30). Of these, L15 mice were chosen, because they had a low, but consistent, number of mGFP-labeled cells within the CA1 area of the hippocampus (73)(74)(75). Three-month-old Adnp-GFP mice were treated for nine consecutive days with either intraperitoneal NAP injection (0.4 μg) diluted in 0.1 ml saline or with 0.1 ml saline as a vehicle.…”

Section: Methodsmentioning

confidence: 99%

Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome

Hacohen-Kleiman

Sragovich

Karmon

et al. 2018

Journal of Clinical Investigation

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164

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Previous findings showed that in mice, complete knockout of activity-dependent neuroprotective protein (ADNP) abolishes brain formation, while haploinsufficiency (Adnp+/-) causes cognitive impairments. We hypothesized that mutations in ADNP lead to a developmental/autistic syndrome in children. Indeed, recent phenotypic characterization of children harboring ADNP mutations (ADNP syndrome children) revealed global developmental delays and intellectual disabilities, including speech and motor dysfunctions. Mechanistically, ADNP includes a SIP motif embedded in the ADNP-derived snippet drug candidate NAP (NAPVSIPQ, also known as CP201), which binds to microtubule end-binding protein 3, essential for dendritic spine formation. Here, we established a unique neuronal membrane-tagged, GFP-expressing Adnp+/- mouse line allowing in vivo synaptic pathology quantification. We discovered that Adnp deficiency reduced dendritic spine density and altered synaptic gene expression, both of which were partly ameliorated by NAP treatment. Adnp+/-mice further exhibited global developmental delays, vocalization impediments, gait and motor dysfunctions, and social and object memory impairments, all of which were partially reversed by daily NAP administration (systemic/nasal). In conclusion, we have connected ADNP-related synaptic pathology to developmental and behavioral outcomes, establishing NAP in vivo target engagement and identifying potential biomarkers. Together, these studies pave a path toward the clinical development of NAP (CP201) for the treatment of ADNP syndrome.

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Section: Methodsmentioning

confidence: 99%

Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome

Hacohen-Kleiman

Sragovich

Karmon

et al. 2018

Journal of Clinical Investigation

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164

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“…It should be noted that the vehicles themselves may affect the activities of microglia/macrophage as well. For instance, dendritic polyglycerol sulfate (dPGS), as a polyglycerol scaffold, has been proved to be able to inhibit microglia activation in chronic inflammation [114]. Iron oxide nanoparticles could reportedly inhibit the production of IL1-β when microglial cells were activated with LPS in vitro [106].…”

Section: 2 Targeting Microglia/macrophages and Tams In The Cnsmentioning

confidence: 99%

Targeting specific cells in the brain with nanomedicines for CNS therapies

Zhang¹,

Lin²,

Kannan

et al. 2016

Journal of Controlled Release

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Treatment of Central Nervous System (CNS) disorders still remains a major clinical challenge. The Blood-brain-barrier (BBB), known as the major hindrance, greatly limits therapeutics penetration into the brain. Moreover, even though some therapeutics can cross BBB based on their intrinsic properties or via the use of proper nanoscale delivery vehicles, their therapeutic efficacy is still often limited without the specific uptake of drugs by the cancer or disease-associated cells. As more studies have started to elucidate the pathological roles of major cells in the CNS (for example, microglia, neurons, and astrocytes) for different disorders, nanomedicines that can enable targeting of specific cells in these diseases may provide great potential to boost efficacy. In this review, we aim to briefly cover the pathological roles of endothelial cells, microglia, tumor-associated microglia/macrophage, neurons, astrocytes, and glioma in CNS disorders and to highlight the recent advances in nanomedicines that can target specific disease-associated cells. Furthermore, we summarized some strategies employed in nanomedicine to achieve specific cell targeting or to enhance the drug neuroprotective effects in the CNS. The specific targeting at the cellular level by nanotherapy can be a more precise and effective means not only to enhance the drug availability but also to reduce side effects.

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“…Among those, dendritic polyglycerol terminated with sulfate (dPGS) has received much attention because of its high anti-inflammatory potential by blocking selectins (cell adhesion proteins) during disordered immune response. [12][13][14][15] In addition, dPGS is presently discussed for the treatment of neurological 16 or cartilage disorders, 17 as an intrinsic tumor tracer in nanotherapeutics, 18 and as a drug delivery carrier. 19,20 The anti-inflammatory potential of the highly anionic dPGS was traced back to its notable complexation with L-and P-selectin, but not E-selectin, 13,14,21 while electroneutral dPG exhibits a very different response and organic uptake.…”

Section: Introductionmentioning

confidence: 99%

Counterion-Release Entropy Governs the Inhibition of Serum Proteins by Polyelectrolyte Drugs

et al. 2018

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Dendritic polyelectrolytes constitute high potential drugs and carrier systems for biomedical purposes. Still, their biomolecular interaction modes, in particular those determining the binding affinity to proteins, have not been rationalized. We study the interaction of the drug candidate dendritic polyglycerol sulfate (dPGS) with serum proteins using isothermal titration calorimetry (ITC) interpreted and complemented with molecular computer simulations. Lysozyme is first studied as a well-defined model protein to verify theoretical concepts, which are then applied to the important cell adhesion protein family of selectins. We demonstrate that the driving force of the strong complexation, leading to a distinct protein corona, originates mainly from the release of only a few condensed counterions from the dPGS upon binding. The binding constant shows a surprisingly weak dependence on dPGS size (and bare charge) which can be understood by colloidal charge-renormalization effects and by the fact that the magnitude of the dominating counterion-release mechanism almost exclusively depends on the interfacial charge structure of the protein-specific binding patch. Our findings explain the high selectivity of P- and L-selectins over E-selectin for dPGS to act as a highly anti-inflammatory drug. The entire analysis demonstrates that the interaction of proteins with charged polymeric drugs can be predicted by simulations with unprecedented accuracy. Thus, our results open new perspectives for the rational design of charged polymeric drugs and carrier systems.

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Dendritic Polyglycerol Sulfate Inhibits Microglial Activation and Reduces Hippocampal CA1 Dendritic Spine Morphology Deficits

Cited by 42 publications

References 65 publications

Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome

Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome

Targeting specific cells in the brain with nanomedicines for CNS therapies

Counterion-Release Entropy Governs the Inhibition of Serum Proteins by Polyelectrolyte Drugs

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