Publications by authors named "David W Hampton"

13 Publications

  • Page 1 of 1

CNS macrophages differentially rely on an intronic enhancer for their development.

Development 2020 12 15;147(23). Epub 2020 Dec 15.

UK Dementia Research Institute at The University of Edinburgh, Chancellor's Building, Edinburgh EH16 4SB, UK

The central nervous system hosts parenchymal macrophages, known as microglia, and non-parenchymal macrophages, collectively termed border-associated macrophages (BAMs). Microglia, but not BAMs, were reported to be absent in mice lacking a conserved enhancer: the -intronic regulatory element (FIRE). However, it is unknown whether FIRE deficiency also impacts BAM arrival and/or maintenance Here, we show that macrophages in the ventricular system of the brain, including Kolmer's epiplexus macrophages, are absent in mice. Stromal choroid plexus BAMs are also considerably reduced. During normal development, we demonstrate that intracerebroventricular macrophages arrive from embryonic day 10.5, and can traverse ventricular walls in embryonic slice cultures. In embryos, the arrival of both primitive microglia and intracerebroventricular macrophages was eliminated, whereas the arrival of cephalic mesenchyme and stromal choroid plexus BAMs was only partially restricted. Our results provide new insights into the development and regulation of different CNS macrophage populations.
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http://dx.doi.org/10.1242/dev.194449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758622PMC
December 2020

HspB5 Activates a Neuroprotective Glial Cell Response in Experimental Tauopathy.

Front Neurosci 2020 11;14:574. Epub 2020 Jun 11.

Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, United Kingdom.

Progressive neuronal death during tauopathies is associated with aggregation of modified, truncated or mutant forms of tau protein. Such aggregates are neurotoxic, promote spreading of tau aggregation, and trigger release of pro-inflammatory factors by glial cells. Counteracting such pathogenic effects of tau by simultaneously inhibiting protein aggregation as well as pro-inflammatory glial cell responses would be of significant therapeutic interest. Here, we examined the use of the small heat-shock protein HspB5 for this purpose. As a molecular chaperone, HspB5 counteracts aggregation of a wide range of abnormal proteins. As a TLR2 agonist, it selectively activates protective responses by CD14-expressing myeloid cells including microglia. We show that intracerebral infusion of HspB5 in transgenic mice with selective neuronal expression of mutant human P301S tau has significant neuroprotective effects in the superficial, frontal cortical layers. Underlying these effects at least in part, HspB5 induces several potent neuroprotective mediators in both astrocytes and microglia including neurotrophic factors and increased potential for removal of glutamate. Together, these findings highlight the potentially broad therapeutic potential of HspB5 in neurodegenerative proteinopathies.
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http://dx.doi.org/10.3389/fnins.2020.00574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300208PMC
June 2020

A single systemic inflammatory insult causes acute motor deficits and accelerates disease progression in a mouse model of human tauopathy.

Alzheimers Dement (N Y) 2019 9;5:579-591. Epub 2019 Oct 9.

Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.

Introduction: Neuroinflammation, which contributes to neurodegeneration, is a consistent hallmark of dementia. Emerging evidence suggests that systemic inflammation also contributes to disease progression.

Methods: The ability of systemically administered lipopolysaccharide (LPS - 500 μg/kg) to effect acute and chronic behavioural changes in C57BL/6 and P301S tauopathy mice was assessed. Markers of pathology were assessed in the brain and spinal cord.

Results: P301S mice display regional microgliosis. Systemic LPS treatment induced exaggerated acute sickness behaviour and motor dysfunction in P301S mice compared with wild-type controls and advanced the onset and accelerated chronic decline. LPS treatment was associated with increased tau pathology 24 hours after LPS injection and spinal cord microgliosis at the end stage.

Discussion: This is the first demonstration that a single systemic inflammatory episode causes exaggerated acute functional impairments and accelerates the long-term trajectory of functional decline associated with neurodegeneration in a mouse model of human tauopathy. The findings have relevance to management of human dementias.
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http://dx.doi.org/10.1016/j.trci.2019.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804509PMC
October 2019

Neurons and neuronal activity control gene expression in astrocytes to regulate their development and metabolism.

Nat Commun 2017 05 2;8:15132. Epub 2017 May 2.

Deanery of Biomedical Sciences, Edinburgh Medical School, University of Edinburgh, Edinburgh EH8 9XD, UK.

The influence that neurons exert on astrocytic function is poorly understood. To investigate this, we first developed a system combining cortical neurons and astrocytes from closely related species, followed by RNA-seq and in silico species separation. This approach uncovers a wide programme of neuron-induced astrocytic gene expression, involving Notch signalling, which drives and maintains astrocytic maturity and neurotransmitter uptake function, is conserved in human development, and is disrupted by neurodegeneration. Separately, hundreds of astrocytic genes are acutely regulated by synaptic activity via mechanisms involving cAMP/PKA-dependent CREB activation. This includes the coordinated activity-dependent upregulation of major astrocytic components of the astrocyte-neuron lactate shuttle, leading to a CREB-dependent increase in astrocytic glucose metabolism and elevated lactate export. Moreover, the groups of astrocytic genes induced by neurons or neuronal activity both show age-dependent decline in humans. Thus, neurons and neuronal activity regulate the astrocytic transcriptome with the potential to shape astrocyte-neuron metabolic cooperation.
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http://dx.doi.org/10.1038/ncomms15132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418577PMC
May 2017

Neurodegeneration progresses despite complete elimination of clinical relapses in a mouse model of multiple sclerosis.

Acta Neuropathol Commun 2013 Dec 23;1:84. Epub 2013 Dec 23.

Centre for Clinical Brain Sciences, MS Centre, University of Edinburgh Chancellor's Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK.

Background: [corrected] Multiple Sclerosis has two clinical phases reflecting distinct but inter-related pathological processes: focal inflammation drives the relapse-remitting stage and neurodegeneration represents the principal substrate of secondary progression. In contrast to the increasing number of effective anti-inflammatory disease modifying treatments for relapse-remitting disease, the absence of therapies for progressive disease represents a major unmet clinical need. This raises the unanswered question of whether elimination of clinical relapses will prevent subsequent progression and if so how early in the disease course should treatment be initiated. Experimental autoimmune encephalomyelitis in the Biozzi ABH mouse recapitulates the clinical and pathological features of multiple sclerosis including relapse-remitting episodes with inflammatory mediated demyelination and progressive disability with neurodegeneration. To address the relationship between inflammation and neurodegeneration we used an auto-immune tolerance strategy to eliminate clinical relapses in EAE in a manner analogous to the clinical effect of disease modifying treatments.

Results: By arresting clinical relapses in EAE at two distinct stages, early and late disease, we demonstrate that halting immune driven demyelination even after the first major clinical event is insufficient to prevent long-term neurodegeneration and associated gliosis. Nonetheless, early intervention is partially neuroprotective, whereas later interventions are not. Furthermore early tolerisation is also associated with increased remyelination.

Conclusions: These findings are consistent with both a partial uncoupling of inflammation and neurodegeneration and that the regenerative response of remyelination is negatively correlated with inflammation. These findings strongly support the need for early combinatorial treatment of immunomodulatory therapies and neuroprotective treatments to prevent long-term neurodegeneration in multiple sclerosis.
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http://dx.doi.org/10.1186/2051-5960-1-84DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895761PMC
December 2013

Focal immune-mediated white matter demyelination reveals an age-associated increase in axonal vulnerability and decreased remyelination efficiency.

Am J Pathol 2012 May 15;180(5):1897-905. Epub 2012 Mar 15.

Euan MacDonald Centre for Motor Neurone Disease Research, Centre for Neuroregeneration, University of Edinburgh, Edinburgh, United Kingdom.

In addition to being an established risk factor for neurodegenerative diseases, age is increasingly recognized as adversely influencing regeneration. Accumulating evidence also suggests that age plays important, although poorly understood, roles with respect to course and prognosis in the degenerative and untreatable later phase of multiple sclerosis. Two experimental models of multiple sclerosis have been particularly influential in modeling the different aspects of neuronal injury and regeneration: global experimental autoimmune encephalomyelitis and focal toxin-mediated injury. Against this background, we report a focal model of immune-mediated demyelinating injury that reliably generates targeted primary demyelination and axonal injury. A detailed pathologic characterization of this model, modified extensively from an earlier study, showed that aged adult animals exhibited increased vulnerability to axonal injury and reduced efficiency of remyelination compared with younger animals. More important, remyelination in aged animals was predominantly Schwann cell mediated, in contrast to the central oligodendrocyte-mediated remyelination that predominated in younger rodents. Together, these findings establish an experimental platform to further study the influence of age on injury and repair in a biologically relevant model of human demyelinating injury.
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http://dx.doi.org/10.1016/j.ajpath.2012.01.018DOI Listing
May 2012

Cell-mediated neuroprotection in a mouse model of human tauopathy.

J Neurosci 2010 Jul;30(30):9973-83

Euan MacDonald Centre for Motor Neurone Disease Research, Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.

Tau protein in a hyperphosphorylated state makes up the intracellular inclusions of several neurodegenerative diseases, including Alzheimer's disease and cases of frontotemporal dementia. Mutations in Tau cause familial forms of frontotemporal dementia, establishing that dysfunction of tau protein is sufficient to cause neurodegeneration and dementia. Transgenic mice expressing human mutant tau in neurons exhibit the essential features of tauopathies, including neurodegeneration and abundant filaments composed of hyperphosphorylated tau. Here we show that a previously described mouse line transgenic for human P301S tau exhibits an age-related, layer-specific loss of superficial cortical neurons, similar to what has been observed in human frontotemporal dementias. We also show that focal neural precursor cell implantation, resulting in glial cell differentiation, leads to the sustained rescue of cortical neurons. Together with evidence indicating that astrocyte transplantation may be neuroprotective, our findings suggest a beneficial role for glial cell-based repair in neurodegenerative diseases.
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http://dx.doi.org/10.1523/JNEUROSCI.0834-10.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6633376PMC
July 2010

An experimental model of secondary progressive multiple sclerosis that shows regional variation in gliosis, remyelination, axonal and neuronal loss.

J Neuroimmunol 2008 Sep 30;201-202:200-11. Epub 2008 Jul 30.

Cambridge Centre for Brain Repair, University of Cambridge, ED Adrian Building, Forvie Site, Robinson Way, Cambridge, CB2 2PY. UK.

Multiple sclerosis (MS) represents a considerable challenge to experimentally model due to its twin pathologies of inflammatory demyelination and neurodegeneration along with its multifocal and multiphasic nature. Experimental autoimmune encephalomyelitis (EAE) in Biozzi ABH mice has previously been shown to reproduce many clinical features also found in secondary progressive MS. In this study we sought to characterise the pathology of chronic EAE in ABH mice. In addition to marked gliosis, we report substantial demyelination, remyelination and axonal and neuronal loss. Together with the clinical pattern, our findings identify chronic EAE as an excellent model of secondary progressive multiple sclerosis.
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http://dx.doi.org/10.1016/j.jneuroim.2008.05.034DOI Listing
September 2008

A potential role for bone morphogenetic protein signalling in glial cell fate determination following adult central nervous system injury in vivo.

Eur J Neurosci 2007 Dec;26(11):3024-35

ICORD, University of British Columbia, Vancouver, BC, Canada.

Bone morphogenetic proteins (BMPs) and their endogenous inhibitors, including noggin, chordin and follistatin, have roles in pattern formation and fate specification of neuronal and glial cells during nervous system development. We have examined their influence on glial reactions in the injured central nervous system (CNS). We show that penetrating injuries to the brain and spinal cord resulted in the upregulation of BMP-2/4, BMP-7, and noggin, with the latter being expressed almost exclusively by reactive astrocytes at the injury site, and we show that astrocytes in vitro produce noggin. As BMPs have been shown to drive cultured NG2-positive oligodendrocyte precursors (OPCs) towards a multipotential phenotype (type II astrocytes), we investigated the effects of inhibiting noggin with a function-blocking antibody (noggin-FbAb). In vitro, BMP-driven conversion of OPCs to type 2 astrocytes was inhibited by noggin, an effect that was reversed by noggin-FbAb. Noggin-FbAb also increased the number of type 2 astrocytes generated from cultured OPCs exposed to an astrocyte feeder layer, consistent with astrocytes producing both BMPs and noggin. In knife cut injuries in vivo, noggin-FbAb treatment resulted in an increase in the number of NG2-positive cells and small GFAP-positive cells in the injury site, and the appearance of glial cells with the morphological and antigenic characteristics of type 2 astrocytes (as generated in vitro), with coexpression of both GFAP and NG2. This potential conversion of inhibitory OPCs to type 2 astrocyte-like cells in vivo suggests that endogenous BMPs, unmasked by noggin antagonism, might be exploited to manipulate cell fate following CNS trauma.
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http://dx.doi.org/10.1111/j.1460-9568.2007.05940.xDOI Listing
December 2007

Spinally upregulated noggin suppresses axonal and dendritic plasticity following dorsal rhizotomy.

Exp Neurol 2007 Mar 22;204(1):366-79. Epub 2006 Dec 22.

ICORD, University of British Columbia, 6270 University Blvd., Vancouver, BC, Canada V6T 1Z4.

Bone morphogenetic proteins (BMPs) and their antagonists, including noggin, are required for nervous system development, but their potential roles in the reactions of the adult central nervous system to injury are unknown. Here we have examined the expression of noggin and BMPs in the spinal cord following dorsal rhizotomy. Through the use of a function-blocking antibody, we have also investigated the role of endogenous noggin in the neuritic plasticity which follows rhizotomy. Dorsal rhizotomy resulted in the upregulation of BMPs 2/4, 7 and noggin in the superficial white matter and in the dorsal neuropil of the spinal cord. These co-localized with glial fibrillary acidic protein, indicating their expression by astrocytes. Because BMPs induce dendritic sprouting and synaptogenesis in some neuronal populations in vitro, we hypothesized that administration of a noggin function-blocking antibody (FbAb) in vivo would augment rhizotomy-induced sprouting in the spinal cord. Topical application of noggin-FbAb to the dorsal surface of the spinal cord following rhizotomy resulted in significant increases in the density of microtubule-associated protein 2 (MAP-2) and substance P (SP)-positive processes within the lateral spinal nucleus. In the deafferented dorsal horn, noggin-FbAb treatment induced significant increases in the density of SP, calcitonin gene-related peptide (CGRP)- and 5-hydroxytryptamine (5-HT)-positive axons. These results suggest a novel mechanism by which endogenous plasticity of spared axons is suppressed following dorsal rhizotomy, and which might be exploited to improve the outcome of spinal cord injury and other CNS trauma.
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http://dx.doi.org/10.1016/j.expneurol.2006.11.017DOI Listing
March 2007

Identification of unique reciprocal and non reciprocal cross packaging relationships between HIV-1, HIV-2 and SIV reveals an efficient SIV/HIV-2 lentiviral vector system with highly favourable features for in vivo testing and clinical usage.

Retrovirology 2005 Sep 16;2:55. Epub 2005 Sep 16.

Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK.

Background: Lentiviral vectors have shown immense promise as vehicles for gene delivery to non-dividing cells particularly to cells of the central nervous system (CNS). Improvements in the biosafety of viral vectors are paramount as lentiviral vectors move into human clinical trials. This study investigates the packaging relationship between gene transfer (vector) and Gag-Pol expression constructs of HIV-1, HIV-2 and SIV. Cross-packaged vectors expressing GFP were assessed for RNA packaging, viral vector titre and their ability to transduce rat primary glial cell cultures and human neural stem cells.

Results: HIV-1 Gag-Pol demonstrated the ability to cross package both HIV-2 and SIV gene transfer vectors. However both HIV-2 and SIV Gag-Pol showed a reduced ability to package HIV-1 vector RNA with no significant gene transfer to target cells. An unexpected packaging relationship was found to exist between HIV-2 and SIV with SIV Gag-Pol able to package HIV-2 vector RNA and transduce dividing SV2T cells and CNS cell cultures with an efficiency equivalent to the homologous HIV-1 vector however HIV-2 was unable to deliver SIV based vectors.

Conclusion: This new non-reciprocal cross packaging relationship between SIV and HIV-2 provides a novel way of significantly increasing bio-safety with a reduced sequence homology between the HIV-2 gene transfer vector and the SIV Gag-Pol construct thus ensuring that vector RNA packaging is unidirectional.
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http://dx.doi.org/10.1186/1742-4690-2-55DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1253535PMC
September 2005

Delivery of a lentiviral vector in a Pluronic F127 gel to cells of the central nervous system.

Eur J Pharm Biopharm 2005 Oct 8;61(3):126-33. Epub 2005 Sep 8.

Department of Medicine, University of Cambridge, Addenbrookes Hospital, Cambridge, UK.

Lentiviral vectors have been demonstrated as efficient tools for gene delivery to the CNS. We describe a novel approach for vector delivery using the thermoresponsive Gel, Pluronic F127 as a carrier. A HIV-1 lentiviral vector expressing GFP was contained in various concentrations of gel (15, 30 and 40%) and applied to cultures of 293T cells. FACS analysis of cells transduced with 8ng of lentiviral vector revealed a similar transduction efficiency for each Gel concentration compared to vector added to cells without PF127. Primary Rat CNS mixed glial cultures were also transduced with lentiviral vector in 15% Pluronic F127 and results demonstrated a similar transduction efficiency of astrocytes compared to virus without gel and no evidence of cell toxicity or death. Stereotaxic delivery of viral vector in 15% PF127 to the rat brain resulted in transduction of cells, predominantly astrocytes close to the injection site. Pluronic F127 gel delivery of viral vectors to the CNS may provide a platform for localised release particularly in areas of brain or spinal cord injury.
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http://dx.doi.org/10.1016/j.ejpb.2005.06.006DOI Listing
October 2005