Neurological diseases: Advancements in live-cell analysis

Neurological disease pathophysiology and injury is incredibly complex and temporally dynamic. This offers an overwhelming challenge in developing and appropriately using physiologically relevant models in investigative research.

Small variations occur on a continual basis, and the processes of degeneration can affect cell function and health over time. Kinetic changes of these types offer a challenge in capturing, quantifying, and interpreting, but they harbor valuable clues for comprehension of disease pathology, identifying therapeutic targets, and characterizing drug pharmacology.

Further complications are added by the limitations of neurological models and their use. This was featured in a recent editorial, “Neurological disease models made clear”.¹ The editorial requested for authors to submit further information regarding the models used and why they were selected. This demonstrates the need for improved characterization of neurological models, their performance, and their limitations.

Real-time kinetic studies can provide verifiable information and are key when it comes to neurological models. They link small alterations in cell health and function, whether caused by disease or therapeutic intervention, with observable phenotypic effects.

This information can improve comprehension of identifying therapeutic targets, disease etiology, and the characterization of drug mechanisms. In addition, there is a need to maintain cellular integrity during an experiment.

This is an advantage in terms of requests for greater emphasis on rigor and reproducibility for in vitro models. Live-cell analysis can be utilized to monitor the function and health of cell lines, allowing the detection of small, cumulative alterations that could lead to undesirable phenotypic effects over time with increased passage.

Image Credit: Sartorius

This report focuses on using the Incucyte^® Live-Cell Analysis System in neurological disease model development, as well as the study of disease pathology, nervous system injury, neuroinflammation, and drug discovery.

This system makes use of real-time, automated analysis and imaging, in combination with microplate throughput, to provide kinetic measurements of cellular health, function, cell number, and neurite outgrowth, among others.

Several investigators have already started the incorporation of live-cell analysis into experimental workflows. Key information has been uncovered, and novel functional insights cross the length of neurological conditions. Timely work such as this fills the void in our comprehension of the dynamic changes found in neurological disease development and system repair.

Integrating real-time kinetic monitoring and cell health measures into experimental workflows can assist the development and interpretation of neurological disease models that are more biologically relevant. This technology better equips researchers to expand the web of neurological disease, expedite workflow, and help in the discovery and analysis of new therapeutics.

Neurological disease model development and refinement

Challenges with disease models

A great array of in vitro and in vivo models have been used in neurological research to investigate cell growth activities, debris clearance, regeneration, morphological changes, genetic regulation, and drug targets.

Models contain positive and negative features, and choosing the correct model system or combination deserves careful consideration.¹ Animal models are costly over time and are limited in translational relevance, leading contemporary efforts to humanize translational research with in vitro models that are more able to recapitulate the complexity of human diseases.

The creation and use of human pluripotent stem cells (hPSC) have offered translational research new hope for the ability to develop models that are more biologically relevant, which opens the door to exploring the development of cells for personalized therapeutics and lineage reprogramming.²

There remain considerations to address for in vitro cell lines, such as the need for homogeneity of an expandable cell line, cell synchronization to a post-mitotic state, and phenotypic evidence of a mature neuron.³ Furthermore, issues can occur with long-term cultures with increasing passage, including cell cross-contamination, selective pressures, misidentification, and genetic drift that can change cell health and function and confound the results.⁴

Refinement and comparison of models

In vitro neurological models may be combined with live-cell imaging and analysis of cell health, function, and morphology to gain important insights into their comparison and improvement.

In neurological diseases, such as MS and Alzheimer’s, Microglia have been implicated. A recent study characterized and optimized primary microglia culture.^5,6 Utilizing live-cell analysis, the phagocytosis of myelin debris by microglia was measured in the context of exposing microglia to serum, as is possible when the barrier between blood and brain is affected (i.e., stroke or contusion).

The data demonstrated that serum exposure increased the phagocytic activity of microglia and that the effect was intrinsic and sustained. This could be attributed to a larger factor(s) that would not be able to traverse an intact blood-brain barrier but could if the barrier was compromised.

Further studies attempted to optimize microglial culture by exploring three methods for their isolation from mouse brain: shaking, trypsinization, and MACS^® sorting with CD11b microbeads.⁷

The MACS^®-isolated primary cells and BV2 cells were sequenced and made subject to transcriptional profiling, which offered a potential difference in chemotaxis between them. This was made valid by measuring the chemotactic migration toward C5a, created by Incucyte^® Live-Cell Imaging and Analysis of Incucyte^® 96-Well Clearview Plates.

The primary microglia showed enhanced migration when compared to BV-2 cell line cells, exposing a significant difference between the models. This demonstrates how live-cell imaging and analysis can be useful in examining certain characteristics of models for a greater understanding of model performance for model selection.

Development of new models

New models are continually being developed to better recapitulate disease mechanisms, particularly when attempting to elucidate patient-specific genetic factors. This process can be added to through the incorporation of live-cell analysis into the workflow to find dynamic changes that could go unnoticed.

Systems for purifying and culturing retinal ganglion cells (RGC) for in vitro use have been developed to study RGC and regenerative medicine applications.⁸ Incucyte^® Neurotrack Analysis Software was utilized to analyze and measure neurite outgrowth of RGCs from 3D retinal organoids, unmasking an increase in neurite length over time, out to 90 h following plating.

The long-term culture of RGCs could be helpful in the study of neuroprotective drugs for glaucoma with added applications for transplantation therapy. The activity of miR-146 (involved in neurodevelopmental disorders) in the differentiation and neural lineage determination of neural stem cells has been investigated.⁹

Expression analysis from autism spectrum disorder (ASD), post-mortem human brain samples were used in combination with in vitro functional data from human NSC (neural stem cells) altered to overexpress miR-146.

The Incucyte^® Live-Cell Analysis System and Incucyte^® Annexin V Dye were utilized for collecting proliferation (confluence) and apoptosis data from H9 human NSC cells that overexpressed miR-146a, and to conduct differentiation analysis. The proliferation rate lowered with greater dendritic branching and extension.

This implies that miR-146a upregulation may disrupt normal transcription, potentially having an impact on cortical disorganization, neuron numbers, and dendritic spine density, which are noted in morphological changes in autism spectrum disorder (ASD).

Live-cell analysis was also used to investigate neurite outgrowth of neuronal and astrocytic abnormalities caused by human-derived α-syn aggregates in a model of Parkinson’s disease with Lewy Body particles.¹⁰

Even basic output measures, like confluence and growth assessment, are capable of yielding important information when strategically added to experimental model design. The confluence and growth has been measured to evaluate the effects of genetic manipulation from CRISPR/Cas9-assisted gene targeting on NSC.¹¹ This resulted in potential new research on CNS development and pathology through the performance of scalable genome editing in a neural stem cell model. Together, these studies showcase that live-cell imaging and analysis can be used to characterize new models that explore disease genetics.

Human pluripotent stem cell models

Live-cell imaging and analysis can be used to measure a range of parameters when developing human induced pluripotent stem cell models, which are becoming popular because of their ability to recapitulate patient-specific phenotypes. Their capability for generating several cell types and a large capacity for self-renewal also make them an enticing option for use in high-throughput drug screening.¹²

Neurite length and branch points were studied by measurement on human-induced pluripotent stem cells (hiPSCs), where the crosslinking agent, genipin, was introduced to fibrin scaffolds.¹³ The genipin-crosslinked fibrin scaffolds had improved neurite outgrowth and offered more stability, with potential applications in 3D printing.

A further example is the migratory behavior of human cortical neurons derivative of human induced pluripotent stem cells (hiPSCs), which were captured through the use of live-cell imaging from a lissencephaly patient sample when compared to control, offering new data on human CNS development and brain formation.¹⁴

A further attempt was made to develop a 3D spinal cord induction model for studying spinal cord development using hPSCs.¹⁵ Through the use of DF Brightfield (a proprietary optical technique for capturing images with an extended depth of field) time-lapse imaging, the Incucyte^® Spheroid Analysis Software Module was cleverly used to take images of differentiating hPSCs to help with model characterization.

The model displayed induction of dorsal and ventral interneurons and could generate centers resembling roof plates. In another experiment, iPSC neural progenitors were combined with inducible gene expression with ex vivo cell engineering, resulting in a method of modulating GDNF secretion.¹⁶

GDNF could be reversed or induced with doxycycline in human-induced pluripotent stem cells that were derivative of neural progenitors.

Live-cell analysis was utilized to evaluate reporter kinetics by acquiring live-cell images of human iNPCs (human-induced pluripotent stem cell-derived neural progenitor cells) that had been nucleofected and grown with luciferin.

Nucleofected iNPCs were also transplanted in vivo into NOD-SCID mice brains to study gene induction. This new methodology may be used in protein delivery for neuroprotection.

In a Nature Medicine publication exploring the genetic engineering of hPSCs, it was found that Cas9 can instigate double-strand breaks lethal to human hPSCs.¹⁷ Confluency for toxicity studies was quantified through Incucyte^® Live-Cell Analysis, with the toxicity found to be dependent on P53/TPS3.

Cas9 toxicity could potentially cause issues throughout engineering that involve clonal expansion, as P53 mutations may develop over time. This could cause problems when CRISPR/Cas9 is utilized in the production of hPSCs meant for cell replacement therapies.

Together, incorporating live-cell analysis with human pluripotent stem cell models offers significant information useful in model assessment for factors such as migration, neurite outgrowth, and assessment of genetic manipulations.

Neurological disease mechanisms and pathology

Real-time tracking of experimental manipulations can offer insights that could be missed with traditional methods. A cell culture method was developed to study proteolytic fragmentation of apoE, which is significant in clearing β-amyloid (Aβ) and neuronal signaling.¹⁸

Live-cell imaging and analysis were utilized to evaluate confluence and neurite length in SH-SY5Y neuroblastoma cell lines. Full-length apoE was used to stimulate neuritogenesis, and a 25-kDa apoE fragment was monitored by HtrA1 under physiological conditions and found to have a neurotrophic function.

In 2017, PAS (plasminogen activation system) clearance of large, pathological protein aggregates from the body was examined.¹⁹ The viability of mouse brain cells and lymph node cultures were measured throughout the interaction of PGPFs (cytotoxic plasmin-generated protein fragments) incubated with clusterin (CLU) and 2-macroglobulin.

Cytotoxicity was metered in EOC 13.31 (microglial-like) and SVEC4-10 (endothelial-like) cells with live-cell imaging and analysis.

Clusterin and 2-macroglobulin were bound to the PGPS to limit toxicity. This integrated analysis proposes that the plasminogen activation system, in conjunction with extracellular chaperone proteins, could enhance clearing of protein aggregates.

Neuroinflammation and neuroprotection

Neuroinflammation is a combination of complexities found in the nervous and immune systems, so it is beneficial to make use of an assortment of kinetic measurements to evaluate this process. The question of whether binding of human recombinant IgM antibody (HIgM22) could denote injured myelin for phagocytic clearance by microglia in multiple sclerosis (MS) has been examined.²⁰ Live-cell imaging and analysis unveiled that IgM stimulated phagocytic activity.

In combination with other research, it was revealed that this process needs actin polymerization, activity of the IgM Fc domain, and CR3 (Complement Receptor 3).

Live-cell analysis has been used in an ischemic stroke model to explore the part of RhoA in T cell transmigration.²¹

The migration rate of RhoA−/− T-cells was less quick than RhoA+/+ T-cell across the endothelial cell layer, similar to what is seen in the BBB (blood-brain barrier), which can correspond to severity of the disease.

There was a reduction in T-cell transmigration with atorvastatin and fasudil treatment, without Rho expression, which was attributed to a more global inhibition of the RhoA-ROCK pathway. Live-cell analysis was also used in a study of the inclusion of RhoA in T cell activation and explored in an animal model of MS.²²

Live-cell analysis can be useful in characterizing neuroprotection and neuroinflammation. An HSV (Herpes Simplex Virus) study examined the reasons that this viral infection is not typically associated with peripheral nerve destruction.²³

Long-term kinetic imaging of cultivated human fetal DRG neurons was carried out using an IL-17c gradient, NGF, or BDNF. Neurite length and an assortment of branch points were evaluated with the Incucyte^® Neurotrack Analysis Software Module.

Human IL-17c stood in as a neurotrophic cytokine through stimulation of neurite outgrowth and branching, reducing apoptosis, and providing a neuroprotective function throughout HSV reactivation.

The study of a variant of TREM 2 receptor (R47H TREM2, linked to Alzheimer’s disease) was undertaken utilizing a TRM2 R47H transgenic mouse model and TREM-2 activating antibody.²⁴

Live-cell analysis assisted in evaluating confluence of macrophages, microglia, BMDM (Bone Marrow Derived Macrophages), and microglia invasion as a response to the TREM2 antibody. The antibody was the cause of heightened signaling in wild type (WT) myeloid cell function.

Nervous system injury

Further work is required to improve our comprehension of nervous system repair and the creation of therapies that are more effective. Kinetic information, cell health measures, and phagocytosis for debris clearance are of particular importance in regenerative studies.

Strategies to encourage myelin clearance after CNS injury have been an area of study.²⁵

In this study, Schwann cells derived from a mouse sciatic nerve crush model were cultured in medium with pHrodo^® -labeled crude PNS myelin.

The phagocytosis of myelin of the Schwann cell was measured utilizing the Incucyte^® Live-Cell Analysis System. Two phagocytic receptors, Axl and Mertk (TAM family of receptor tyrosine kinases) were needed to clear the myelin debris, engaging both Schwann cell-mediated myelin clearance and autophagy.

This clarified the pathways engaged in myelin clearance subsequent to CNS injury, and introduced new roads for therapeutic development. Also explored was transcription factor manipulation for neuron regeneration, with testing to see if KLF7 is able to regenerate DPSN axons and form synapses after injury to the spinal cord.²⁶

The effect of AAV-KLF7 on neurite outgrowth on rat neurons was tested in this in vitro study. Incucyte^® measurements of neurite outgrowth exposed drastic increases in neurite length and branch points. An in vivo mouse model was used to further explore this, where mice were exposed to a T10 contusion injury and subsequent treatment with AAV-KLF7. KLF7 was expressed in the injured spinal cord, and the treatment saw improvements to a number of output measures, including muscle weight and the regeneration of axons and synapses, as well as motor function recovery, as evaluated by the animal’s ability to walk a grid.

This study shows how in vitro model evaluation utilizing live-cell analysis can serve to guide translational experimental design when assessing therapeutic potential in vivo.

Identification of drug targets and therapeutic development

Drug screening

It is possible to refine neurological models through use of live-cell imaging and analysis, which can lead to improvements when choosing targets for drug screening.

In a recent Nature Communications paper, Jin et al. developed an in vitro screening method for anti-Aβ antibody drug candidates for Alzheimer’s disease treatment, which could assist in developing more effective immunotherapies.²⁷

The aim was to offer greater information about the ability of antibody candidates to recognize toxic Aβ. Using an aggregate-preferring mAB, IC22, binding of this agent was compared against two murine precursors of bapineuzumab (mAb 3D6) and solanezumab (mAb 266).

A sensitive bioassay was developed that combined the utilization of brain extracts from AD brain extracts with Incucyte^® Live-Cell Imaging and Analysis of induced neurons (iN) from human iPSCs generated through modification of the Ngn2 protocol.²⁸

Measurement baselines were recorded for the iNs, with a raise in neurite length and branch points measured using Incucyte^® HD phase contrast imaging. This timeframe was also associated with rises in tau, GluA1, synapsin 1, synaptophysin 1, and PSD-95.

The neurons were subsequently treated with Aβ-rich soluble AD brain extracts and the live-cell imaging completed a second time, unveiling a time- and dose-dependent reduction in neurite length and branch points on the identical cells as those utilized in the baseline.

The IC22 antibody, 3D6, and 266 were subsequently also tested through this quantitative method, with live-cell analysis incorporated to evaluate neurotoxicity.

IC22 protected the iPSC-derived human neurons from human Aβ toxicity with greater effectiveness than 3D6 (bapineuzaumab) or 266 (solanezumab). This study offered new and enticing methodology for therapeutic antibody screening in drug discovery, with potential for faster screening of therapeutic antibodies for diseases like AD.

The use of live-cell imaging and analysis to measure neurotoxicity and attenuation made this method more quantitative. This has potential for incorporation into the mathematical estimation of antibody levels needed to neutralize the toxic Aβ and possible dosing.

With respect to toxic amyloid fractions, a gentle homogenization technique to separate toxic Aβ oligomers prepared from post-mortem AD human brain extracts was further developed.²⁹ Here, live-cell analysis assisted in collecting phase contrast images of iPSC-derived human neurons that were exposed to toxic Aβ oligomers in the brain extract, and subsequent measuring of the cell bodies and processes of the neurites with the Incucyte^® Neurotrack Analysis Software Module.

The diffusible, toxic Aβ fraction, isolated through gentle extraction, maintained the neurotoxic activity as measured by a lowering in neurite length, with a temporal concordance to a reduction in plasticity measured by LTP recording (Long-Term Potentiation).

The isolation of this toxic Aβ could allow for target selection that is more effective, which further emphasizes the value of live-cell analysis and incorporating functional assays into research workflows.

Identifying drug targets

Live-cell imaging and analysis is useful in identifying drug targets for a range of other diseases, which emphasizes the impact of quantitative kinetic outputs. An investigation into reducing the abundance of cytotoxic defective protein from the HTT gene in Huntington’s disease (HD) showed that two positive modulators of mHTT, HIPK3 and MAPK11, would modulate HTT levels in vitro and in vivo.³⁰ The Incucyte^® Live-Cell Analysis System helped with assessing confluence (cell shrinkage and death), and the measuring of Capsase-3 activity of Q73 neurons.

Potential new drug targets for HD were discovered along with new ways to consider target discovery. A live-cell analysis combined with gene expression in one study used a model of HCMV (human cytomegalovirus) to demonstrate that a novel drug candidate, artemisone, acted more quickly in the viral replication cycle than a traditional ganciclovir treatment.³¹

Further studies have investigated HDAC inhibition for neuroinflammation and neurodegenerative disease, the effect of lithium on Schwann cells, and the functional analysis of mutations of GRIN2a (NMDR gene) in epilepsy-aphasia syndrome (EAS) patients.^{32, 33, 34}

Examining drug toxicity

Quantitative measurements can be used together to arrive at treatment effects on average cell health and function. Using an AD mouse model, an investigation into the use of an isoform-selective p38α MAPK inhibitor, MW150 was conducted.

A number of Incucyte^® live-cell assays applications were used to research responsiveness to MW150 in a BV2, a murine microglial cell line, including proliferation (confluence), migration, phagocytosis of BV2 cells and their response to MW150.³⁵

The study demonstrated that MW150 was capable of modulating the neuroinflammatory responses in a decisive manner with no negative impairing of the microglia physiological functions (proliferation, migration, and phagocytosis).

Identifying new therapeutic applications

Lastly, live-cell analysis can offer information on ways that existing, approved medications could be used in new therapeutic areas. It has been shown that somatostatin (SST) is a possible therapeutic for AD by protecting the organization of tight junction proteins (TJP), maintaining the blood-brain barrier from injury caused by Aβ, and regulating LRP1 and RAGE expression.³⁶

The Incucyte^® Live-Cell Analysis System and Incucyte^® Caspase 3/7 Green Dye were useful in measuring apoptosis in hCMEC/ D3 cells treated with Aβ1-42 with or without SST.

Cells treated with Aβ1-42 + SST demonstrated a dose-dependent lowering of Caspase-3/7 in comparison to cells treated with just Aβ1-42, suggesting drug inhibition on caspase activity as a mechanism. Patient-specific, in vitro models of microglia-mediated synapse and neural progenitor cell (NPC) engulfment have also been created to explore the contributions of C4 in microglia-mediated pruning.³⁷

Reprogrammed, microglia-like cells (hiMGS) and monocyte-derived macrophages were co-cultured with pHrodo-labeled synaptosomes and NPCs (neural progenitor cells) and imaged in real-time with the Incucyte^® Live-Cell Analysis System, and revealed a rise in phagocytosis of synaptic structures and NPCs by the microglia-like cells, as well as reduced uptake by macrophages.

Cells were subsequently treated with C4, which is implicated in schizophrenia, and the engulfment of synaptic structures was noted.

This model proposes the potential for creating patient specific models that are amenable to drug screening. These examples together demonstrate the advantage of applying live-cell kinetic analysis to re-visit mechanisms of action for existing drugs and the creation of new screening assays. The results can be used to guide further research investigations.

Resources and further reading

Introduction

1. No authors listed, Editorial. Neurological disease models made clear. Nat Med, Sep;21(9);964 (2015) 

Neurological disease model development and refinement

2. Ferreira LM and Mostajo-Radji MA. How induced pluripotent stem cells are redefining personalized medicine. Gene, May 10;520(1);1-6 (2013)
3. Schlachetzki JC, Saliba SW, and Oliveira AC. Studying neurodegenerative diseases in culture models. Rev Bras Psiquiatr, 35 Suppl 2;S92-100 (2013)
4. Hughes P, et al. The costs of using unauthenticated over-passaged cell lines: how much more data do we need? Biotechniques, Nov;43(5); 575-582 (2018)
5. Ransohoff RM and El Khoury J. Microglia in Health and Disease made clear. Cold Spring Harb Perspect Biol, Sep 9;8(1);a020560 (2015)
6. Bohlen CJ, et al. Diverse requirements for microglial survival, specification, and function revealed by defined medium cultures. Neuron, May 17;94(4); 759-773.e8 (2017)
7. He Y, et al. RNA sequencing analysis reveals quiescent microglia isolation methods from postnatal mouse brains and limitations of BV2 cells. J Neuroinflammation, May 22;1 (1);153 (2018)
8. Kobayashi W, et al. Culture systems of dissociated mouse and human pluripotent stem cell-derived retinal ganglion cells purified by two-step immunopanning. Invest Ophthalmol Vis Sci, Feb 1;5 (2);776-787 (2018)
9. Nguyen LS, et al. Role of miR-146a in neural stem cell differentiation and neural lineage determination: relevance for neurodevelopmental disorders. Mol Autism, Jun 19;9;38 (2018)
10. Cavaliere F, et al. In vitro α-synuclein neurotoxicity and spreading among neurons and astrocytes using Lewy body extracts from Parkinson disease brains. Neurobiol Dis, Jul;103;101-112 (2017)
11. Bressan RB, et al. Efficient CRISPR/Cas9- assisted gene targeting enables rapid and precise genetic manipulation of mammalian neural stem cells. Development, Feb 15;144(4);635-648 (2017)
12. Zhu Z and Huangfu D. Human pluripotent stem cells: an emerging model in developmental biology. Development, (Cambridge, England), 140(4);705-717 (2013)
13. Robinson M, Douglas S, and Michelle Willerth S. Mechanically stable fibrin scaffolds promote viability and induce neurite outgrowth in neural aggregates derived from human induced pluripotent stem cells. Sci Rep, Jul 24;7(1);6250 (2017)
14. Bamba Y, et al. Visualization of migration of human cortical neurons generated from induced pluripotent stem cells. J Neurosci Methods, Sep 1;289;57-63 (2017)
15. Ogura T, Sakaguchi H, Miyamoto S, and Takahashi J. Three-dimensional induction of dorsal, intermediate and ventral spinal cord tissues from human pluripotent stem cells. Development, Jul 30;145(16) (2018)
16. Akhtar AA, et al. Inducible Expression of GDNF in Transplanted iPSC-Derived Neural Progenitor Cells. Stem Cell Reports, Jun 5;10(6);1696-1704 (2018)
17. Ihry RJ, et al. p53 inhibits CRISPR-Cas9 engineering in human pluripotent stem cells. Nat Med, Jul;24(7); 939-946 (2018)

Neurological disease mechanisms and pathology

18. Muñoz SS, et al. The serine protease HtrA1 contributes to the formation of an extracellular 25-kDa apolipoprotein E fragment that stimulates neuritogenesis. J Biol Chem, Mar 16;293(11);4071-4084 (2018)
19. Constantinescu P, et al. Amorphous protein aggregates stimulate plasminogen activation, leading to release of cytotoxic fragments that are clients for extracellular chaperones. J Biol Chem, Sep 1;292(35);14425-14437 (2017

Neuroinflammation

20. Zorina Y, et al. Human IgM antibody rHIgM22 promotes phagocytic clearance of myelin debris by microglia. Sci Rep, Jun 20;8(1);9392 (2018)
21. Manresa-Arraut, A, et al. RhoA Drives T-Cell Activation and Encephalitogenic Potential in an Animal Model of Multiple Sclerosis. Front Immunol, May 31;9;1235 (2018)
22. Manresa-Arraut A, et al. RhoA-ROCK pathway is important for T-Cell migration in a mouse stroke model. Journal of Translational Neurosciences, Dec;(2) No.1:3;1-9 (2017)
23. Peng T, et al. Keratinocytes produce IL-17c to protect peripheral nervous systems during human HSV- 2 reactivation. J Exp Med, Aug 7;214(8);2315-2329 (2017)
24. Cheng Q, et al. TREM2-activating antibodies abrogate the negative pleiotropic effects of the Alzheimer’s disease variant Trem2R47H on murine myeloid cell function. J Biol Chem, Aug 10;293(32);12620-12633 (2018) 

Nervous system injury

25. Brosius Lutz A, et al. Schwann cells use TAM receptor mediated phagocytosis in addition to autophagy to clear myelin in a mouse model of nerve injury. Proc Natl Acad Sci USA, Sep19;114(38);E8072-E8080 (2017)
26. Li WY, et al. AAV-KLF7 promotes descending propriospinal neuron axonal plasticity after spinal cord injury. Neural Plast, 2017;1621629 (2017)

Identification of drug targets and therapeutic development

27. Jin, M, et al. An in vitro paradigm to assess potential anti-Aβ antibodies for Alzheimer’s disease. Nat Commun, Jul 11;9(1);2676 (2018)
28. Zhang Y, et al. Rapid single-step induction of functional neurons from human pluripotent stem cells. Neuron, 78(5);785-798 (2013)
29. Hong W, et al. Diffusible, highly bioactive oligomers represent a critical minority of soluble Aβ in Alzheimer’s disease brain. Acta Neuropathol, Jul;136(1);19-40 (2018)
30. Yu M, et al. Suppression of MAPK11 or HIPK3 reduces mutant Huntingtin levels in Huntington’s disease models. Cell Res, Dec;27(12);1441–1465 (2017)
31. Oiknine-Djian E, et al. The artemisinin derivative artemisone is a potent inhibitor of human cytomegalovirus replication. Antimicrob Agents Chemother, Jun 26;62(7) (2018)
32. Durham BS, Grigg R, and Wood IC. Inhibition of histone deacetylase 1 or 2 reduces induced cytokine expression in microglia through a protein synthesis independent mechanism. J Neurochem, Oct;143(2); 214-224 (2017)
33. Piñero G, et al. Lithium reversibly inhibits Schwann cell proliferation and differentiation without inducing myelin loss. Mol Neurobiol, Dec;54(10); 8287-8307 (2017)
34. Addis L, et al. Epilepsy-associated GRIN2A mutations reduce NMDA receptor trafficking and agonist potency - molecular profiling and functional rescue. Sci Rep, Feb 27;7(1);66 (2017)
35. Zhou Z, et al. Retention of normal glia function by an isoform-selective protein kinase inhibitor drug candidate that modulates cytokine production and cognitive outcomes. J Neuroinflammation, 14;75 (2017)
36. Paik S, Somvanshi RK, and Kumar U. Somatostatin Maintains Permeability and Integrity of Blood-Brain Barrier in β-Amyloid Induced Toxicity. Mol Neurobiol, Apr 26 (2018)
37. Sellgren CM, et al. Patient-specific models of microglia mediated engulfment of synapses and neural progenitors. Mol Psychiatry, Feb;22(2) (2017)

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