History of Neuroscience: Mesoglia and Microglia

Microglia are mononuclear phagocytes that reside within the central nervous system (CNS). They differ from macroglia (astrocytes and oligodendrocytes) in terms of their origin, phenotype and functions, but more closely resemble tissue-resident macrophages in all these aspects. The principal role of microglia is to provide a first line of defence against pathological insults at this primary site. Modern consensus holds that microglia are of myeloid origin, much like tissue-resident mononuclear phagocytes within other organs, and arise during fetal development from progenitors in the yolk sac, liver or spleen or from mesenchymal tissues surrounding the nervous system that subsequently seed the CNS during gestation and perinatally, and differentiate morphologically to ramified and immunophenotypically suppressed adult varieties (20, 31). These intriguing and controversial cells have been the focus of intense scientific research for the past two decades, and the subject of many recent reviews to which the reader is referred (8, 11, 12, 14-16, 18, 20-22, 24-27, 31-34, 54-57)

Impact of age-related neuroglial cell responses on hippocampal deterioration

Aging is one of the greatest risk factors for the development of sporadic age-related neurodegenerative diseases and neuroinflammation is a common feature of this disease phenotype. In the immunoprivileged brain, neuroglial cells, which mediate neuroinflammatory responses, are influenced by the physiological factors in the microenvironment of the central nervous system (CNS). These physiological factors include but are not limited to cell-to-cell communication involving cell adhesion molecules, neuronal electrical activity and neurotransmitter and neuromodulator action. However, despite this dynamic control of neuroglial activity, in the healthy aged brain there is an alteration in the underlying neuroinflammatory response notably seen in the hippocampus, typified by astrocyte/microglia activation and increased pro-inflammatory cytokine production and signaling. These changes may occur without any overt concurrent pathology, however, they typically correlate with deteriorations in hippocamapal or cognitive function. In this review we examine two important phenomenons, firstly the relationship between age-related brain deterioration (focusing on hippocampal function) and underlying neuroglial response(s), and secondly how the latter affects molecular and cellular processes within the hippocampus that makes it vulnerable to age-related cognitive decline

Dynamic expression of Dab2 in the mouse embryonic central nervous system

<p>Abstract</p> <p>Background</p> <p>Dab2, one of two mammalian orthologs of <it>Drosophila Disabled</it>, has been shown to be involved in cell positioning and formation of visceral endoderm during mouse embryogenesis, but its role in neuronal development is not yet fully understood. In this report, we have examined the localization of the Dab2 protein in the mouse embryonic central nervous system (CNS) at different developmental stages.</p> <p>Results</p> <p>Dab2 protein was transiently expressed in rhombomeres 5 and 6 of the developing hindbrain between E8.5 and E11.5, and in the floor plate of the neural tube from E9.5 to E12.5, following which it was no longer detectable within these regions. Dab2 protein was also identified within circumventricular organs including the choroid plexus, subcommissural organ and pineal gland during their early development. While Dab2 was still strongly expressed in the adult choroid plexus, immunoreactivity within the subcommissural organ and pineal gland was lost after birth. In addition, Dab2 was transiently expressed within a subpopulation of Iba1-positive mononuclear phagocytes (including presumed microglial progenitors) within the neural tube from E10.0 and was lost by E14.5. Dab2 was separately localized to Iba1 positive cells from E9.5 and subsequently to F4/80 positive cells (mature macrophage/myeloid-derived dendritic cells) positioned outside the neural tube from E12.5 onwards, implicating Dab2 expression in early cells of the mononuclear phagocyte lineage. Dab2 did not co-localize with the pan-neuronal marker PGP9.5 at any developmental stage, suggesting that Dab2 positive cells in the developing CNS are unlikely to be differentiating neurons.</p> <p>Conclusion</p> <p>This is the first study to demonstrate the dynamic spatiotemporal expression of Dab2 protein within the CNS during development.</p

Glial cells are functionally impaired in juvenile neuronal ceroid lipofuscinosis and detrimental to neurons.

The neuronal ceroid lipofuscinoses (NCLs or Batten disease) are a group of inherited, fatal neurodegenerative disorders of childhood. In these disorders, glial (microglial and astrocyte) activation typically occurs early in disease progression and predicts where neuron loss subsequently occurs. We have found that in the most common juvenile form of NCL (CLN3 disease or JNCL) this glial response is less pronounced in both mouse models and human autopsy material, with the morphological transformation of both astrocytes and microglia severely attenuated or delayed. To investigate their properties, we isolated glia and neurons from Cln3-deficient mice and studied their basic biology in culture. Upon stimulation, both Cln3-deficient astrocytes and microglia also showed an attenuated ability to transform morphologically, and an altered protein secretion profile. These defects were more pronounced in astrocytes, including the reduced secretion of a range of neuroprotective factors, mitogens, chemokines and cytokines, in addition to impaired calcium signalling and glutamate clearance. Cln3-deficient neurons also displayed an abnormal organization of their neurites. Most importantly, using a co-culture system, Cln3-deficient astrocytes and microglia had a negative impact on the survival and morphology of both Cln3-deficient and wildtype neurons, but these effects were largely reversed by growing mutant neurons with healthy glia. These data provide evidence that CLN3 disease astrocytes are functionally compromised. Together with microglia, they may play an active role in neuron loss in this disorder and can be considered as potential targets for therapeutic interventions

Expression of chemokines and their receptors by human brain endothelium: Implications for multiple sclerosis

Leukocyte migration into the CNS is mediated by chemokines, expressed on the surface of brain endothelium. This study investigated the production of chemokines and expression of chemokine receptors by human brain endothelial cells (HBEC), in vitro and in situ in multiple sclerosis tissue. Four chemokines (CCL2, CCL5, CXCL8 and CXCL10), were demonstrated in endothelial cells in situ, which was reflected in the chemokine production by primary HBEC and a brain endothelial cell line, hCEMC/D3. CXCL8 and CCL2 were constitutively released and increased in response to TNF and/or IFN . CXCL10 and CCL5 were undetectable in resting cells but were secreted in response to these cytokines. TNF strongly increased the production of CCL2, CCL5 and CXCL8, while IFN up-regulated CXCL10 exclusively. CCL3 was not secreted by HBECs and appeared to be confined to astrocytes in situ. The chemokine receptors CXCR1 and CXCR3 were expressed by HBEC both in vitro and in situ, and CXCR3 was up-regulated in response to cytokine stimulation in vitro. By contrast, CXCR3 expression was reduced in silent MS lesions. Brain endothelium expresses particularly high levels of CXCL10 and CXCL8, which may account for the predominant TH1-type inflammatory reaction seen in chronic conditions such as multiple sclerosis

Efficacy of low-fat milk and yogurt fortified with vitamin D<inf>3</inf> on systemic inflammation in adults with abdominal obesity

Background The prevalence of vitamin D deficiency is increasing globally and is associated with an increased risk of metabolic syndrome, autoimmune disease, and cardiovascular disease. Vit D deficiency is also associated with increased systemic inflammation. The current study aimed to determine the efficacy of low-fat milk and yogurt fortified with 1500 IU nano-encapsulated vitamin D, on systemic inflammation in abdominal obese participants. Method This multi-center study was conducted using a 2.5-month parallel total-blind randomized clinical trial design. Two hundred and eighty nine subjects were allocated to four groups: low-fat milk fortified by 1500 IU nano-encapsulated vitamin D3 (200 mL/day). Simple milk (200 mL/day), low-fat yogurt fortified by 1500 IU nano-encapsulated vitamin D3 (150 g/day), and simple yogurt (150 g/day). Results The results showed that serum levels of neutrophils, lymphocytes, platelets and red blood cell distribution width (RDW) were significantly lower before and after the intervention in fortified dairy groups. The results showed that serum levels of neutrophils, lymphocytes, platelets, and RDW before and after intervention in the fortified dairy groups were significantly lower (p < 0.05). The values of = neutrophil to lymphocyte ratio (NLR), platelets to lymphocyte ratio, and RDW to platelets ratio (RPR) reduced significantly in the fortification group (p < 0.05). Conclusion Fortification with nano-encapsulated vitamin D3 of dairy products may decrease inflammation in individuals with abdominal obesity

Alteration of Blood–Brain Barrier Integrity by Retroviral Infection

The blood–brain barrier (BBB), which forms the interface between the blood and the cerebral parenchyma, has been shown to be disrupted during retroviral-associated neuromyelopathies. Human T Lymphotropic Virus (HTLV-1) Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is a slowly progressive neurodegenerative disease associated with BBB breakdown. The BBB is composed of three cell types: endothelial cells, pericytes and astrocytes. Although astrocytes have been shown to be infected by HTLV-1, until now, little was known about the susceptibility of BBB endothelial cells to HTLV-1 infection and the impact of such an infection on BBB function. We first demonstrated that human cerebral endothelial cells express the receptors for HTLV-1 (GLUT-1, Neuropilin-1 and heparan sulfate proteoglycans), both in vitro, in a human cerebral endothelial cell line, and ex vivo, on spinal cord autopsy sections from HAM/TSP and non-infected control cases. In situ hybridization revealed HTLV-1 transcripts associated with the vasculature in HAM/TSP. We were able to confirm that the endothelial cells could be productively infected in vitro by HTLV-1 and that blocking of either HSPGs, Neuropilin 1 or Glut1 inhibits this process. The expression of the tight-junction proteins within the HTLV-1 infected endothelial cells was altered. These cells were no longer able to form a functional barrier, since BBB permeability and lymphocyte passage through the monolayer of endothelial cells were increased. This work constitutes the first report of susceptibility of human cerebral endothelial cells to HTLV-1 infection, with implications for HTLV-1 passage through the BBB and subsequent deregulation of the central nervous system homeostasis. We propose that the susceptibility of cerebral endothelial cells to retroviral infection and subsequent BBB dysfunction is an important aspect of HAM/TSP pathogenesis and should be considered in the design of future therapeutics strategies

Microglia in the human nervous system during development

Microglia are the principal resident mononuclear phagocytes of the central nervous system (CNS). They are representatives of the immune system intrinsic to this organ. These cells are morphologically, phenotypically and functionally distinct from other populations of mononuclear phagocytes associated with the CNS, such as perivascular macrophages, supraependymal macrophages, epiplexus cells of the choroid plexus and meningeal macrophages. While the origin of microglia has been the subject of controversy for many years, the prevailing view holds that they are derived from mesenchyme (mesodermal elements) or from circulating blood mononuclear progenitors (monocytes) that penetrate the nervous tissues early in development. This article will review the location, distribution, morphology and phenotype of microglia in the developing human CNS. Potential functional roles for microglia are discussed in relation to developmental events

The neuropathology of autism - neuronal cytoarchitectural alterations and glial cell responses

Structural and pathological abnormalities affecting the brainstem (particularly the olivary nuclei), cerebellum, limbic system (hippocampus and amygdala) and the neocortex have been described to varying degrees in cases of autism examined at post-mortem (Palmen et al. 2004). Evidence for neurodevelopmental disturbances in autism may be further derived from reports of altered brain volume (megalencephaly), cortical dysgenesis and abnormalities in neuronal alignment within the cerebral cortex, as well as cytoarchitectural changes within the amygdala (with fewer neurons particularly in the lateral nucleus), and the cerebellum (loss of Purkinje neurons). Preliminary reports have also suggested that white matter abnormalities, neuroinflammation (Vargas et al. 2005), neuroglial activation (Vargas et al. 2005; Rezaie et al. 2006) and oxidative stress are further components associated with autism. Nevertheless, with the exception of Purkinje cell loss within the cerebellum (which is not in itself a pathological hallmark for autism), the neuropathology of autism still remains largely undefined, with inconsistent findings possibly reflecting (i) interindividual differences (the autism spectrum), (ii) analysis of small sample sizes, (iii) biases in results (co-occurrence of epilepsy, ‘high’ or ‘low’-functioning status, and pathology related to agonal changes pre-mortem), and/or (iv) aetio-pathological differences in the development of the condition (i.e. altered development of a distributed neural network involving a number of brain regions or ‘systems’ rather than localised, neurodevelopmental alterations). For the past few years, we have been investigating aspects of the neuropathology of autism in cohorts of individuals whose brain had been donated for research, to the MRC London Neurodegenerative Diseases Brain Bank at the Institute of Psychiatry in the UK, and the Autism Tissue Program (ATP) in the US. The ATP was established in 1998 to oversee and manage brain donations related to neurological research in autism in the US (Pickett 2001; Pickett and London 2005). Research data from studies utilising these precious resources are integrated into a database – the ATP Informatics Portal (Brimacombe et al. 2007), which enables detailed targeted comparison of neurological and neuroinformatic data to be accessed for each individual case and cross-referenced. Together with other investigators, we are engaged in a collaborative research effort referred to as the ‘ATP Brain Atlas Project’ which attempts to address questions relating to the neuropathology of autism in a defined cohort of cases. Our ongoing collaborative studies have been funded by the National Alliance for Autism Research (NAAR) and are currently funded by Autism Speaks. Our findings in relation to (i) minicolumnar arrangements within the neocortex (Poster 9; Casanova et al. 2006), (ii) neuronal cytoarchitectural alterations within the fusiform gyrus, and (iii) glial cell responses within the cerebral cortex in autism, will be presented at the meeting. Brimacombe MB et al. (2007) Autism post-mortem neuroinformatic resource: the autism tissue program (ATP) informatics portal. J Autism Dev Disord 37: 574-579. Casanova MF et al. (2006) Minicolumnar abnormalities in autism. Acta Neuropathol 112: 287-303. Palmen SJ et al. (2004) Neuropathological findings in autism. Brain 127: 2572-2583. Pickett J (2001) Current investigations in autism brain tissue research. J Autism Dev Disord 31: 521-527. Pickett J, London E (2005) The neuropathology of autism: a review. J Neuropathol Exp Neurol 64: 925-935. Rezaie P et al. (2006) Assessment of glial cell reactivity within the frontal lobe in autism. Neuropathol Appl Neurobiol 32:226-227. Vargas DL et al. (2005) Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 57: 67-81