Who fans the flames of Alzheimer's disease brains? Misfolded tau on the crossroad of neurodegenerative and inflammatory pathways

Neurodegeneration, induced by misfolded tau protein, and neuroinflammation, driven by glial cells, represent the salient features of Alzheimer's disease (AD) and related human tauopathies. While tau neurodegeneration significantly correlates with disease progression, brain inflammation seems to be an important factor in regulating the resistance or susceptibility to AD neurodegeneration. Previously, it has been shown that there is a reciprocal relationship between the local inflammatory response and neurofibrillary lesions. Numerous independent studies have reported that inflammatory responses may contribute to the development of tau pathology and thus accelerate the course of disease. It has been shown that various cytokines can significantly affect the functional and structural properties of intracellular tau. Notwithstanding, anti-inflammatory approaches have not unequivocally demonstrated that inhibition of the brain immune response can lead to reduction of neurofibrillary lesions. On the other hand, our recent data show that misfolded tau could represent a trigger for microglial activation, suggesting the dual role of misfolded tau in the Alzheimer's disease inflammatory cascade. On the basis of current knowledge, we can conclude that misfolded tau is located at the crossroad of the neurodegenerative and neuroinflammatory pathways. Thus disease-modified tau represents an important target for potential therapeutic strategies for patients with Alzheimer's disease

Differentiation of mouse bone marrow derived stem cells toward microglia-like cells

<p>Abstract</p> <p>Background</p> <p>Microglia, the macrophages of the brain, have been implicated in the causes of neurodegenerative diseases and display a loss of function during aging. Throughout life, microglia are replenished by limited proliferation of resident microglial cells. Replenishment by bone marrow-derived progenitor cells is still under debate. In this context, we investigated the differentiation of mouse microglia from bone marrow (BM) stem cells. Furthermore, we looked at the effects of FMS-like tyrosine kinase 3 ligand (Flt3L), astrocyte-conditioned medium (ACM) and GM-CSF on the differentiation to microglia-like cells.</p> <p>Methods</p> <p>We assessed <it>in vitro-</it>derived microglia differentiation by marker expression (CD11b/CD45, F4/80), but also for the first time for functional performance (phagocytosis, oxidative burst) and <it>in situ </it>migration into living brain tissue. Integration, survival and migration were assessed in organotypic brain slices.</p> <p>Results</p> <p>The cells differentiated from mouse BM show function, markers and morphology of primary microglia and migrate into living brain tissue. Flt3L displays a negative effect on differentiation while GM-CSF enhances differentiation.</p> <p>Conclusion</p> <p>We conclude that <it>in vitro-</it>derived microglia are the phenotypic and functional equivalents to primary microglia and could be used in cell therapy.</p

Targeting neuroinflammation for therapeutic intervention in neurodegenerative pathologies: A role for the peptide analogue of thymulin (PAT)

Introduction: Inflammation has a vital task in protecting the organism, but when deregulated, it can have serious pathological consequences. The central nervous system (CNS) is capable of mounting immune and inflammatory responses, albeit different from that observed in the periphery. Neuroinflammation, however, can be a major contributor to neurodegenerative diseases and constitute a major challenge for medicine and basic research. Areas covered: Both innate and adaptive immune responses normally play an important role in homeostasis within the CNS. Microglia, astrocytes and neuronal cells express a wide array of toll-like receptors (TLR) that can be upregulated by infection, trauma, injuries and various exogenic or endogenic factors. Chronic hyper activation of brain immune cells can result in neurotoxic actions due to excessive production of several pro-inflammatory mediators. Several studies have recently described an important role for targeting receptors such as nicotinic receptors located on cells in the CNS or in other tissues for the control of inflammation. Expert opinion: Thymulin and its synthetic peptide analogue (PAT) appear to exert potent anti-inflammatory effects at the level of peripheral tissues as well as at the level of the brain. This effect involves, at least partially, the activation of cholinergic mechanisms. © 2012 Informa UK, Ltd

Morphological features of microglial cells in the hippocampal dentate gyrus of Gunn rat: a possible schizophrenia animal model

<p>Abstract</p> <p>Background</p> <p>Schizophrenia is a debilitating and complex mental disorder whose exact etiology remains unknown. There is growing amount of evidence of a relationship between neuroinflammation, as demonstrated by microglial activation, and schizophrenia. Our previous studies have proposed that hyperbilirubinemia plays a role in the pathophysiology of schizophrenia. Furthermore, we suggested the Gunn rat, an animal model of bilirubin encephalopathy, as a possible animal model of schizophrenia. However, the effects of unconjugated bilirubin on microglia, the resident immune cell of the CNS, in Gunn rats have never been investigated. In the present study, we examined how microglial cells respond to bilirubin toxicity in adult Gunn rats.</p> <p>Methods</p> <p>Using immunohistochemical techniques, we compared the distribution, morphology, and ultrastructural features of microglial cells in Gunn rats with Wistar rats as a normal control. We also determined the ratio of activated and resting microglia and observed microglia-neuron interactions. We characterized the microglial cells in the hippocampal dentate gyrus.</p> <p>Results</p> <p>We found that microglial cells showed activated morphology in the hilus, subgranular zone, and granular layer of the Gunn rat hippocampal dentate gyrus. There was no significant difference between cell numbers between in Gunn rats and controls. However, there was significant difference in the area of CD11b expression in the hippocampal dentate gyrus. Ultrastructurally, microglial cells often contained rich enlarged rich organelles in the cytoplasm and showed some phagocytic function.</p> <p>Conclusions</p> <p>We propose that activation of microglia could be an important causal factor of the behavioral abnormalities and neuropathological changes in Gunn rats. These findings may provide basic information for further assessment of the Gunn rat as an animal model of schizophrenia.</p

Genetic variants in FGFR2 and FGFR4 genes and skin cancer risk in the Nurses' Health Study

<p>Abstract</p> <p>Background</p> <p>The human fibroblast growth factor (FGF) and its receptor (FGFR) play an important role in tumorigenesis. Deregulation of the <it>FGFR2 </it>gene has been identified in a number of cancer sites. Overexpression of the <it>FGFR4 </it>protein has been linked to cutaneous melanoma progression. Previous studies reported associations between genetic variants in the <it>FGFR2 </it>and <it>FGFR4 </it>genes and development of various cancers.</p> <p>Methods</p> <p>We evaluated the associations of four genetic variants in the <it>FGFR2 </it>gene highly related to breast cancer risk and the three common tag-SNPs in the <it>FGFR4 </it>gene with skin cancer risk in a nested case-control study of Caucasians within the Nurses' Health Study (NHS) among 218 melanoma cases, 285 squamous cell carcinoma (SCC) cases, 300 basal cell carcinoma (BCC) cases, and 870 controls.</p> <p>Results</p> <p>We found no evidence for associations between these seven genetic variants and the risks of melanoma and nonmelanocytic skin cancer.</p> <p>Conclusion</p> <p>Given the power of this study, we did not detect any contribution of genetic variants in the <it>FGFR2 </it>or <it>FGFR4 </it>genes to inherited predisposition to skin cancer among Caucasian women.</p

The Spider Effect: Morphological and Orienting Classification of Microglia in Response to Stimuli in Vivo

The different morphological stages of microglial activation have not yet been described in detail. We transected the olfactory bulb of rats and examined the activation of the microglial system histologically. Six stages of bidirectional microglial activation (A) and deactivation (R) were observed: from stage 1A to 6A, the cell body size increased, the cell process number decreased, and the cell processes retracted and thickened, orienting toward the direction of the injury site; until stage 6A, when all processes disappeared. In contrast, in deactivation stages 6R to 1R, the microglia returned to the original site exhibiting a stepwise retransformation to the original morphology. Thin highly branched processes re-formed in stage 1R, similar to those in stage 1A. This reverse transformation mirrored the forward transformation except in stages 6R to 1R: cells showed multiple nuclei which were slowly absorbed. Our findings support a morphologically defined stepwise activation and deactivation of microglia cells

Neuroinflammation, Mast Cells, and Glia: Dangerous Liaisons

The perspective of neuroinflammation as an epiphenomenon following neuron damage is being replaced by the awareness of glia and their importance in neural functions and disorders. Systemic inflammation generates signals that communicate with the brain and leads to changes in metabolism and behavior, with microglia assuming a pro-inflammatory phenotype. Identification of potential peripheral-to-central cellular links is thus a critical step in designing effective therapeutics. Mast cells may fulfill such a role. These resident immune cells are found close to and within peripheral nerves and in brain parenchyma/meninges, where they exercise a key role in orchestrating the inflammatory process from initiation through chronic activation. Mast cells and glia engage in crosstalk that contributes to accelerate disease progression; such interactions become exaggerated with aging and increased cell sensitivity to stress. Emerging evidence for oligodendrocytes, independent of myelin and support of axonal integrity, points to their having strong immune functions, innate immune receptor expression, and production/response to chemokines and cytokines that modulate immune responses in the central nervous system while engaging in crosstalk with microglia and astrocytes. In this review, we summarize the findings related to our understanding of the biology and cellular signaling mechanisms of neuroinflammation, with emphasis on mast cell-glia interactions

Reduction of astrogliosis and microgliosis by cerebrospinal fluid shunting in experimental hydrocephalus

<p>Abstract</p> <p>Background</p> <p>Reactive gliosis has the potential to alter biomechanical properties of the brain, impede neuronal regeneration and affect plasticity. Determining the onset and progression of reactive astrogliosis and microgliosis due to hydrocephalus is important for designing better clinical treatments.</p> <p>Methods</p> <p>Reactive astrogliosis and microgliosis were evaluated as the severity of hydrocephalus increased with age in hydrocephalic H-Tx rats and control littermates. Previous studies have suggested that gliosis may persist after short-term drainage (shunt treatment) of the cerebrospinal fluid. Therefore shunts were placed in 15d hydrocephalic rats that were sacrificed after 6d (21d of age) or after 21d (36d of age). Tissue was processed for Western blot procedures and immunohistochemistry, and probed for the astrocytic protein, Glial Fibrillary Acidic Protein (GFAP) and for microglial protein, Isolectin B4 (ILB4).</p> <p>Results</p> <p>In the parietal cortex of untreated hydrocephalic animals, GFAP levels increased significantly at 5d and at 12d compared to age-matched control rats. There was a continued increase in GFAP levels over control at 21d and at 36d. Shunting prevented some of the increase in GFAP levels in the parietal cortex. In the occipital cortex of untreated hydrocephalic animals, there was a significant increase over control in levels of GFAP at 5d. This trend continued in the 12d animals, although not significantly. Significant increases in GFAP levels were present in 21d and in 36d animals. Shunting significantly reduced GFAP levels in the 36d shunted group. Quantitative grading of immuno-stained sections showed similar changes in GFAP stained astrocytes.</p> <p>Immuno-stained microglia were altered in shape in hydrocephalic animals. At 5d and 12d, they appeared to be developmentally delayed with a lack of processes. Older 21d and 36d hydrocephalic animals exhibited the characteristics of activated microglia, with thicker processes and enlarged cell bodies. Following shunting, fewer activated microglia were present.</p> <p>Histologic examination of the periventricular area and the periaqueductal area showed similar findings with the 21d and 36d animals having increased populations of both astrocytes and microglia which were reduced following shunting with a more dramatic reduction in the long term shunted animals.</p> <p>Conclusion</p> <p>Overall, these results suggest that reactive astrocytosis and microgliosis are associated with progressive untreated ventriculomegaly, but that shunt treatment can reduce the gliosis occurring with hydrocephalus.</p