130,610 research outputs found
Comprehension du role de la microglie dans les maladies neurodegeneratives a l’aide du modele animal [Understanding the role of microglia in neurodegenerative diseases using the animal model]
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Inflammatory components in human Alzheimer's disease and after active amyloid-β42 immunization
No full textInflammatory processes are important in the pathogenesis of Alzheimer's disease and in response to amyloid-β immunotherapy. We investigated the expression of multiple inflammatory markers in the brains of 28 non-immunized patients with Alzheimer's disease and 11 patients with Alzheimer's disease immunized against amyloid-β42 (AN1792): microglial ionized calcium-binding adaptor Iba-1, lysosome marker CD68, macrophage scavenger receptor A, Fcγ receptors I (CD64) and II (CD32); and also immunoglobulin IgG, complement C1q and the T lymphocyte marker CD3 using immunohistochemistry. The data were analysed with regard to amyloid-β and phospho-tau pathology, severity of cerebral amyloid angiopathy and cortical microhaemorrhages. In non-immunized Alzheimer's disease cases, amyloid-?42 correlated inversely with CD32 and Iba-1, whereas phospho-tau correlated directly with all microglial markers, IgG, C1q and the number of T cells. In immunized Alzheimer's disease cases, amyloid-β42 load correlated directly with macrophage scavenger receptor A-positive clusters and inversely with C1q. The severity of cerebral amyloid angiopathy and microhaemorrhages did not relate to any of the analysed markers. Overall, the levels of CD68, macrophage scavenger receptor A, CD64, CD32 and the number of macrophage scavenger receptor A-positive plaque-related clusters were significantly lower in immunized than non-immunized cases, although there was no significant difference in Iba-1 load, number of Iba-1-positive cells, IgG load, C1q load or number of T cells. Our findings indicate that different microglial populations co-exist in the Alzheimer's disease brain, and that the local inflammatory status within the grey matter is importantly linked with tau pathology. After amyloid-β immunization, the microglial functional state is altered in association with reduced amyloid-β and tau pathology. The results suggest that, in the long term, amyloid-β immunotherapy results in downregulation of microglial activation and potentially reduces the inflammation-mediated component of the neurodegeneration of Alzheimer's disease
Physiopathologie et modeles animaux de l'infection du systeme nerveux central par le VIH [Pathophysiology and animal models of central nervous system infection by HIV]
No full textTransforming growth factor-beta1, the dominant cytokine in murine prion disease: influence on inflammatory cytokine synthesis and alteration of vascular extracellular matrix
No full textPrevious studies from our laboratory have shown the ME7 model of murine scrapie to be accompanied by an atypical inflammatory response that is characterized by marked astroglial and microglial activation but also by the lack of significant expression of the pro-inflammatory cytokines interleukin (IL)-1? and IL-6. The aim of this study was to determine whether, in the absence of IL-1? and IL-6, tumour necrosis factor (TNF)-? may play an equivalent pro-inflammatory role, or if an anti-inflammatory cytokine profile dominates. We have used competitive polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) to determine the levels of TNF-?, IL-10 and transforming growth factor (TGF)-?1 in the ME7 model, using their expression in lipopolysaccharide (LPS)-induced acute inflammation as a positive control. Levels of mRNA were elevated for all three cytokines during acute inflammation, while TGF-?1 mRNA alone was significantly elevated in ME7-injected brains. Similarly, by ELISA, we detected elevated IL-10, TNF-? and TGF-?1 in LPS-injected animals but only significant elevation of TGF-?1 in ME7-injected animals. An increase in laminin and collagen IV deposition around blood vessels was also observed and is consistent with up-regulation by active TGF-?1. These findings suggest that TGF-?1 may play a central role in maintenance of an atypical microglial phenotype and may also be involved in vascular and extracellular matrix change
Review. Activation patterns of microglia and their identification in the human brain
No full textMicroglia in the central nervous system are usually maintained in a quiescent state. When activated, they can perform many diverse functions which may be either beneficial or harmful depending on the situation. Although microglial activation may be accompanied by changes in morphology, morphological changes cannot accurately predict the function being undertaken by a microglial cell. Studies of peripheral macrophages and in vitro and animal studies of microglia have resulted in the definition of specific activation states: M1 (classical activation) and M2 (sometimes subdivided into alternative activation and acquired deactivation). Some authors have suggested that these might be an overlapping continuum of functions rather than discrete categories. In this review, we consider translational aspects of our knowledge of microglia: specifically, we discuss the question as to what extent different activation states of microglia exist in the human central nervous system, which tools can be used to identify them and emerging evidence for such changes in ageing and in Alzheimer's disease
Immunotherapy for Alzheimer's disease and other dementias
No full textPurpose of review: The aim of this article is to review the role of immunotherapy in the removal of proteins which accumulate abnormally in neurodegenerative disorders associated with dementia, in particular amyloid-[beta] accumulation in Alzheimer's disease.Recent findings: In both transgenic mouse models and in two trials of amyloid-[beta] immunotherapy for human Alzheimer's disease, active immunization with amyloid-[beta] 1-42 results in the removal of amyloid-[beta] plaques from the cerebral cortex associated with, in the mouse models, improvement in cognitive function. Cerebral amyloid angiopathy and neurofibrillary tangles persist, however, and there is also concern about T lymphocyte immune reactions in the meninges in the human cases. Active immunization schedules are being developed to minimize T lymphocyte reactions and to maximize antibody production and passive immunization protocols are being devised. Immunotherapy for removal of the proteins which accumulate in other neurodegenerative disorders associated with dementia such as prion proteins and [alpha]-synuclein are in the early stages of development.Summary: Dementias in the elderly are an increasing medical, social and economic problem and current treatments are only effective. In the majority of dementias, proteins accumulate within cells and in the extracellular compartments of the brain. In the most common dementia, Alzheimer's disease, amyloid-[beta] accumulates as plaques in the extracellular space of the grey matter and in artery walls as cerebral amyloid angiopathy and tau protein accumulates as neurofibrillary tangles within neurons
Atypical inflammation in the central nervous system in prion disease
No full textThe inflammatory response in prion diseases is dominated by microglial activation. Contrary to their profile in vitro none of the pro-inflammatory cytokines interleukin-1[beta], interleukin-6, or tumour necrosis factor-[alpha] are significantly upregulated in the ME7 model of prion disease. However, two major inflammatory mediators are elevated: transforming growth factor-[beta]1 and prostaglandin E2. This cytokine profile is the same as that reported for macrophages during phagocytosis of apoptotic cells and indeed transforming growth factor-[beta]1 and prostaglandin E2 are responsible for the downregulated phenotype of these macrophages. Transforming growth factor-[beta]1 may also have roles in extracellular matrix deposition and in amyloidogenesis and may play a direct role in disease pathogenesis. There is also now evidence to suggest that a peripheral infection, and its consequent systemic cytokine expression, may drive central nervous system cytokine expression and perhaps exacerbate disease
Ageing and the accumulation of amyloid in brain parenchyma and blood vessel walls in Alzheimer's disease
No full textNeuropil and neuronal changes in hippocampal NADPH-diaphaorase histochemistry in the ME7 model of murine prion disease
No full textNitric oxide (NO) has been implicated in neurotoxicity and cerebral blood flow changes in chronic neurodegeneration, but its activity in the mammalian prion diseases has not been studied in detail. Nicotine adenine dinucleotide phosphate (NADPH)-diaphorase (NADPH-d) histochemistry is a simple and robust histochemical procedure that allows localization of the tissue distribution of NO synthases. The aim of the present study is to assess whether NADPH-d histochemical activity is altered in the hippocampus in the ME7 model of prion disease in C57BL/6J mice. At early and late stages after the initiation of the disease we assessed features of the NADPH-d positive cells and the neuropil histochemical activity in CA1 and dentate gyrus using densitometric analysis. In C57BL/6J mice 13 weeks postinjection of the prion agent ME7, when behavioural changes first become apparent, neuropil NADPH-d histochemical staining increases, whereas at late stages it decreases dramatically. Both type I and type II NADPH-d positive cells were found to survive throughout the hippocampal formation into the late stages of the disease, but diaphorase activity was reduced in dendritic branches and abnormal varicosities were present in both dendritic and axonal processes of NADPH-d positive type I cells. The pathophysiological implications of the results remain to be investigated but both blood flow alteration and NO neurotoxicity may be features of the diseas
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