Microglia In White Matter Research Articles

Adenosine A 2A receptor deficiency exacerbates white matter lesions and cognitive deficits induced by chronic cerebral hypoperfusion in mice

Adenosine A 2A receptor inactivation consistently protects against acute ischemic brain injury; however, the role of the A 2A receptor in chronic cerebral ischemia is unknown. To elucidate that, chronic cerebral hypoperfusion model was established by permanent stenosis of bilateral common carotid artery in A 2A receptor knock-out mice and their wild-type littermates in this study. White matter lesions were observed after stenosis of common carotid arteries in both A 2A receptor knock-out mice and wild-type mice. The demyelination-related damage and proliferation of astrocytes and microglia in white matter was observed more seriously in A 2A receptor knock-out mice compared with that in wild-type mice. Working memory was also more seriously impaired in A 2A receptor knock-out mice relative to wild-type mice. The mRNA expression and protein level of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) increased more remarkably in the corpus callosum in the A 2A receptor knock-out mice. In conclusion, inactivation of the A 2A receptor exacerbates the white matter lesions and cognitive deficits induced by chronic cerebral hypoperfusion, and this effect may be associated with increased expression of the proinflammatory cytokines in the white matter.

Developmental changes in the expression of chemokine receptor CCR1 in the rat cerebellum.

Chemokines are small, soluble proteins that regulate leukocyte migration, adhesion, and proliferation. Recent evidence suggests that chemokine receptors are expressed in the central nervous system and that their functions extend beyond their roles in inflammation. Specific chemokines and their receptors are implicated in cerebellar development. In this study, we evaluated the expression of beta-chemokine receptor CCR1 in the immature and adult rat cerebellum and report striking developmental changes in CCR1 expression. Reverse transcriptase polymerase chain reaction assays of cerebellum revealed moderate increases in CCR1 mRNA expression from postnatal day (P) 3 to adulthood. Light and confocal microscopy were used to evaluate developmental changes in the neuroanatomical and cell-specific distribution of CCR1 immunoreactivity. CCR1 immunoreactivity was detected as early as P3 and peaked between P7 and P21. The predominant CCR1-immunoreactive neuronal cell types included granule cells of the internal granular layer, Purkinje cells, Golgi cells, and molecular layer interneurons; Bergmann glia, astrocytes, and resting microglia also expressed CCR1. In contrast, granule cells in the external germinal layer, descending granule cells, and activated microglia rarely expressed CCR1. We also evaluated the expression of the CCR1 ligand macrophage inflammatory protein-1alpha (MIP-1alpha/CCL3). Two cell populations expressed MIP-1alpha: physiologically activated microglia in white matter (P7-P14) and Purkinje cells (P7-adult). MIP-1alpha-positive cells were frequently located near the processes and cell bodies of CCR1-immunoreactive cells, during times of neuronal and glial maturation (second and third postnatal weeks). These findings provide support for the hypothesis that CCR1 plays a role in postnatal cerebellar development.

Induction of the dual specificity phosphatase PAC1 in rat brain following seizure activity.

Recurrent seizure activity leads to delayed neuronal death as well as to inflammatory responses involving microglia in hippocampal subfields CA1, CA3 and CA4. Since mitogen activated protein (MAP) kinases control neuronal apoptosis and trigger generation of inflammatory cytokines, their activation state could determine seizure-related brain damage. PAC1 is a dual specificity protein phosphatase inactivating MAP kinases which we have found to be undetectable in normal brain. Despite this, kainic acid-induced seizure activity lead to rapid (approximately 3 h) but transient appearance of PAC1 mRNA in granule cells of the dentate gyrus as well as in pyramidal CA1 neurons. This pattern changed with time and after 2-3 days PAC1 was induced in dying CA1 and CA3 neurons. At this time PAC1 mRNA was also expressed in white matter microglia as well as in microglia invading the damaged hippocampus. PAC1 may play an important role controlling MAP kinase involvement in both neuronal death and neuro-inflammation following excitotoxic damage.

711 White matter microglia produce Gelatinase A and its activator, membrane-type matrix metalloproteinase-1 in human brain tissues

711 White matter microglia produce Gelatinase A and its activator, membrane-type matrix metalloproteinase-1 in human brain tissues

Reactive microgIia in Creutzfeldt‐Jakob disease

Creutzfeldt-Jakob disease (CJD) is characterized by a loss of neurons accompanied by astrogliosis and spongiform changes in the neuropil. It has been recognized that reactive microglia occur in CJD but little is known about the regional distribution and extent of the microglial activation. We have, therefore, examined six brains from cases of sporadic CJD by immunohistochemical labelling of grey and white matter microglia from frontal, parietal, temporal, and occipital lobes, striatum, thalamus, cerebellum and brain stem with RCA-1, LCA, CD68, HLA-DR, and HAM56. Microglial activation occurred in the grey matter where astrogliosis and prion protein (PrP) deposits were prominent. Processes of activated microglia surrounded the outer rim of spongy vacuoles. A diffuse microglial response was seen in the white matter that was immunophenotypically different from grey matter. Double-labelling with microglial markers and anti-PrP showed that activated microglia did not contain PrP-immunoreactivity. Therefore a primary role of microglia in PrP processing seems unlikely. Activated microglia may contribute to neuronal damage in CJD due to their cytotoxic potential.

White matter microglia produce membrane-type matrix metalloprotease, an activator of gelatinase A, in human brain tissues.

Membrane-type matrix metalloprotease (MT-MMP) is an activator of gelatinase A (MMP-2), which has previously been found in carcinoma cells. We examined non-neurological and Alzheimer's disease brain tissues for MT-MMP by immunohistochemistry and in situ hybridization. The anti-MT-MMP antibodies gave positive staining of brain microglial cells in all the brain tissues. Positively stained microglia were found only in the white matter. The cells producing MT-MMP protein were also shown to be white matter microglia. These results provide further evidence that activated gelatinase A, which may be a processing enzyme for degradation of beta-amyloid protein, may be produced in white matter microglia.

White matter microglia produce membrane-type matrix metalloprotease, an activator of gelatinase A, in human brain tissues

White matter microglia produce membrane-type matrix metalloprotease, an activator of gelatinase A, in human brain tissues

Selective localization of gelatinase A, an enzyme degrading beta-amyloid protein, in white matter microglia and in Schwann cells.

Gelatinase A is an enzyme capable of cleaving soluble beta-amyloid protein (beta AP), and may function as an alpha-secretase to produce secretory forms of amyloid precursor protein. We examined gelatinase A immunoreactivity in the brains and posterior roots of neurologically normal, lacunar stroke, Alzheimer disease (AD), amyotrophic lateral sclerosis, progressive supranuclear palsy and myasthenia gravis cases. The gelatinase A antibody stained only microglial cells in the white matter in all the brain tissues. In AD brain, the reactive microglia located in the center of classical senile plaques, as well as in other microglial cells in the gray matter, showed no immunoreactivity. Gelatinase A in white matter microglial cells may play a role in preventing local deposition of beta AP. In the posterior root, Schwann cells had positive immunoreactivity. As with other metalloproteases, gelatinase A in Schwann cells may play an antiproliferative role.

Selective localization of gelatinase A, an enzyme degrading ?-amyloid protein, in white matter microglia and in Schwann cells

Selective localization of gelatinase A, an enzyme degrading ?-amyloid protein, in white matter microglia and in Schwann cells

Immunohistochemistry using antibodies to α-interferon and its induced protein, MxA, in Alzheimer's and Parkinson's disease brain tissues

The localization of α-interferon (α-IFN) and its induced protein, MxA, was examined in human brain tissues from neurologically normal, Alzheimer's disease (AD) and Parkinson's disease (PD) cases. In all cases, a few neurons in the superficial cortical layers and microglial cells in the white matter were stained with the antibody to α-IFN. In AD brains, white matter microglia were intensely labeled for α-IFN and reactive microglia, such as those on senile plaques, were strongly positive for MxA protein. In PD, Lewy bodies in the substantia nigra were positive for MxA, but there was no staining for α-IFN in that region. These results suggest that increased expression of α-IFN in the white matter microglia and appearance of MxA protein in reactive microglia contribute to Alzheimer pathology. The staining of some Lewy bodies for MxA may be indicative of a viral infection or other unknown factor.

Immunohistochemical localization of vitronectin, its receptor and beta-3 integrin in Alzheimer brain tissue

The vitronectin receptor (VNR) is an integrin which consists of an α-subunit which can associate with multiple β-subunits. A polyclonal antibody to this integrin weakly stained resting microglia in white matter of control brain and strongly stained reactive microglia in both gray and white matter of Alzheimer brain. This antibody, as well as a monoclonal antibody to β 3, stained some platelets in capillaries of both control and Alzheimer tissue. When the antiserum was immunoabsorbed with a preparation enriched in the α-chain of the vitronectin receptor, it failed to stain microglial cells, but continued to stain platelets. When it was immunoabsorbed with a peripheral blood platelet preparation, all immunostaining was abolished. These results indicate that the vitronectin receptor of microglia is associated with a β-chain different from β 3, but that β 3 is expressed by some platelets in brain capillaries. An antibody to vitronectin itself stained senile plaques and neurofibrillary tangles in Alzheimer entorhinal cortex, but only residual plasma in control tissue. Senile plaques positive for vitronectin had microglial cores strongly positive for the vitronectin receptor. The high levels of vitronectin receptor on reactive microglia in areas containing extracellular vitronectin suggest the possibility that vitronectin is serving an opsonizing function for microglial phagocytosis.

Immunocytochemical characterisation of the immune reaction in the central nervous system in multiple sclerosis: Possible role for microglia in lesion growth

As there is evidence that in multiple sclerosis T-cell activation occurs in the central nervous system rather than outside, the inflammatory lesion may be extended through antigen presentation by cells at the edge of the plaque. In this study we present an immunocytochemical report on CNS tissue from an active case of MS, with an analysis of the distribution of CD4 and CD8 binding T cells and the expression of class I and II MHC determinants in plaques and white matter. Perivascular cuffs of early lesions, as judged by hypercellularity and minimal demyelination, contained activated T (Tac +) cells, which reacted with an anti-IL-2 monoclonal antibody. Thus sufficient T-cell growth factor would appear to be present to fuel the immune reaction in a growing lesion. The preponderance of T cells of the cytotoxic/suppressor (CD8) phenotype in the CNS parenchyma was found in conjunction with widespread staining of class I MHC antigen, a prerequisite for activity of cytotoxic T cells. Potential antigen presenting cells were demonstrated in MS plaques with a monoclonal antibody against the cytoplasmic, invariant chain of class II MHC. Macrophages and astrocytes, contributed to the staining in the hypercellular plaque border while the distribution of class II + microglia in white matter suggest they may also be of importance in local antigen presentation.