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It is becoming increasingly apparent that disorders of the brain microvasculature contribute to many neurological disorders. In recent years it has become clear that a major player in these events is the capillary pericyte which, in the brain, is now known to control the blood–brain barrier, regulate blood flow, influence immune cell entry and be crucial for angiogenesis. In this review we consider the under‐explored possibility that peripheral diseases which affect the microvasculature, such as hypertension, kidney disease and diabetes, produce central nervous system (CNS) dysfunction by mechanisms affecting capillary pericytes within the CNS. We highlight how cellular messengers produced peripherally can act via signalling pathways within CNS pericytes to reshape blood vessels, restrict blood flow or compromise blood–brain barrier function, thus causing neuronal dysfunction. Increased understanding of how renin–angiotensin, Rho‐kinase and PDGFRβ signalling affect CNS pericytes may suggest novel therapeutic approaches to reducing the CNS effects of peripheral disorders. [ABSTRACT FROM AUTHOR]

In I C9orf72 i BAC transgenic ALS/FTD mice, inhibiting PKR through AAV expression of the dominant negative PKR-K296R protein decreases RAN protein pathology I in vivo i and improves behavioral phenotypes. These data demonstrate RAN proteins play a central role in I C9orf72 i ALS/FTD and describe novel approaches for the treatment of C9 and other RAN-protein diseases. Furthermore, alterations in protein SUMOylation are observed in a wide range of neurological and neurodegenerative diseases, and several extranuclear disease-associated proteins have been shown to be directly SUMOylated. Palmitoylation is a reversible post-translational modification that regulates membrane association, trafficking, and protein-protein interactions. Together these data suggest that a transmissible misfolded protein might play a role, and the prion protein could be directly or indirectly involved in the generation of the subtle MS-like pathology in recipient mice. [Extracted from the article]

Antimicrobial peptides are an important part of the innate immune defense in the central nervous system ( CNS). The expression of the antimicrobial peptides psoriasin (S100A7) is up-regulated during bacterial meningitis. However, the exact mechanisms induced by psoriasin to modulate glial cell activity are not yet fully understood. Our hypothesis is that psoriasin induced pro- and anti-inflammatory signaling pathways as well as regenerative factors to contribute in total to a balanced immune response. Therefore, we used psoriasin-stimulated glial cells and analyzed the translocation of the pro-inflammatory transcription factor nuclear factor 'kappa-light-chain-enhancer' of activated B-cells ( NFκB) in murine glial cells and the expression of pro- and anti-inflammatory mediators by real time RT- PCR, ELISA technique, and western blotting. Furthermore, the relationship between psoriasin and the antioxidative stress transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) was investigated. Stimulation with psoriasin not only enhanced NFκB translocation and increased the expression of the pro-inflammatory cytokines, interleukin-6 ( IL-6) and tumor necrosis factor-α ( TNF- α) but also neurotrophin expression. Evidence for functional interactions between psoriasin and Nrf2 were detected in the form of increased antioxidant response element ( ARE) activity and induction of Nrf2/ ARE-dependent heme oxygenase 1 ( HO-1) expression in psoriasin-treated microglia and astrocytes. The results illustrate the ability of psoriasin to induce immunological functions in glia cells where psoriasin exerts divergent effects on the innate immune response. [ABSTRACT FROM AUTHOR]

Proper brain function in the nervous system relies on the accurate establishment of synaptic contacts during development. Countless synapses populate the adult brain in an orderly fashion. In each synapse, a presynaptic terminal loaded with neurotransmitters-containing synaptic vesicles is perfectly aligned to an array of receptors in the postsynaptic membrane. Presynaptic differentiation, which encompasses the events underlying assembly of new presynaptic units, has seen notable advances in recent years. It is now consensual that as a growing axon encounters the receptive dendrites of its partner, presynaptic assembly will be triggered and specified by multiple postsynaptically-derived factors including soluble molecules and cell adhesion complexes. Presynaptic material that reaches these distant sites by axonal transport in the form of pre-assembled packets will be retained and clustered, ultimately giving rise to a presynaptic bouton. This review focuses on the cellular and molecular aspects of presynaptic differentiation in the central nervous system, with a particular emphasis on the identity of the instructive factors and the intracellular processes used by neuronal cells to assemble functional presynaptic terminals. [ABSTRACT FROM AUTHOR]

The mouse monoclonal antibody marketed as anti-adenomatous polyposis coli clone CC1, often referred to as CC1, is the antibody most commonly used to specifically label mature oligodendrocytes without labeling myelin. Previous studies have shown that despite being raised against adenomatous polyposis coli, this antibody binds another unknown antigen. We show that the CC1 antibody binds Quaking 7, an RNA-binding protein that is highly up-regulated in myelinating oligodendrocytes in the central nervous system. [ABSTRACT FROM AUTHOR]

The role of transcription factor Sox13, which together with Sox5 and Sox6 belongs to the SoxD family, is only poorly characterized in central nervous system development. Therefore, we analysed whether Sox13 expression and function overlaps with or differs from that of its close relatives Sox5 and Sox6. In the developing mouse spinal cord, we found Sox13 predominantly expressed in neuroepithelial precursors, oligodendroglial and astroglial cells. The substantially overlapping expression with Sox5 and Sox6 in oligodendroglial cells prompted us to study potential roles during specification, lineage progression and differentiation of oligodendrocytes. In contrast to Sox5 and Sox6, Sox13 expression continues after differentiation and even increases in myelinating oligodendrocytes. Sox13 deletion did not interfere with oligodendroglial development, which was normal in Sox13-deficient mice. However, the premature differentiation of oligodendrocyte precursors triggered by loss of Sox6 was slightly more prominent in Sox6/Sox13 double-deficient mice. Sox13 can bind to the same sites in myelin gene promoters as Sox5 and Sox6 in vitro. Reporter gene assays furthermore reveal a similar antagonizing effect on Sox10-dependent transactivation of myelin gene promoters as previously shown for Sox5 and Sox6. This argues that Sox13 is functionally redundant with the other SoxD proteins and complements Sox5 and Sox6 in their role as important modulators of oligodendrocyte development. [ABSTRACT FROM AUTHOR]

The bioactivity of neuropeptide Y (NPY) is either N-terminally modulated with respect to receptor selectivity by dipeptidyl peptidase 4 (DP4)-like enzymes or proteolytic degraded by neprilysin or meprins, thereby abrogating signal transduction. However, neither the subcellular nor the compartmental differentiation of these regulatory mechanisms is fully understood. Using mass spectrometry, selective inhibitors and histochemistry, studies across various cell types, body fluids, and tissues revealed that most frequently DP4-like enzymes, aminopeptidases P, secreted meprin-A (Mep-A), and cathepsin D (CTSD) rapidly hydrolyze NPY, depending on the cell type and tissue under study. Novel degradation of NPY by cathepsins B, D, L, G, S, and tissue kallikrein could also be identified. The expression of DP4, CTSD, and Mep-A at the median eminence indicates that the bioactivity of NPY is regulated by peptidases at the interphase between the periphery and the CNS. Detailed ex vivo studies on human sera and CSF samples recognized CTSD as the major NPY-cleaving enzyme in the CSF, whereas an additional C-terminal truncation by angiotensin-converting enzyme could be detected in serum. The latter finding hints to potential drug interaction between antidiabetic DP4 inhibitors and anti-hypertensive angiotensin-converting enzyme inhibitors, while it ablates suspected hypertensive side effects of only antidiabetic DP4-inhibitors application. [ABSTRACT FROM AUTHOR]

Cholinergic neurons in the CNS are involved in synaptic plasticity and cognition. Both muscarinic and nicotinic acetylcholine receptors (nAChRs) influence plasticity and cognitive function. The mechanism underlying nAChR-induced plasticity, however, has remained elusive. Here, we demonstrate morphological changes in dendritic spines following activation of α4β2* nAChRs, which are expressed on glutamatergic pre-synaptic termini of cultured hippocampal neurons. Exposure of the neurons to nicotine resulted in a lateral enlargement of spine heads. This was abolished by dihydro-β-erythroidine, an antagonist of α4β2* nAChRs, but not by α-bungarotoxin, an antagonist of α7 nAChRs. Tetanus toxin or a mixture of 2-amino-5-phosphonovaleric acid and 6-cyano-7-nitroquinoxaline-2,3-dione, antagonists of NMDA- and AMPA-type glutamate receptors, blocked the nicotine-induced spine remodeling. In addition, nicotine exerted full spine-enlarging response in the post-synaptic neuron whose β2 nAChR expression was knocked down. Finally, pre-treatment with nicotine enhanced the Ca2+-response of the neurons to glutamate. These data suggest that nicotine influences the activity of glutamatergic neurotransmission through the activation of pre-synaptic α4β2 nAChRs, resulting in the modulation of spinal architecture and responsiveness. The present findings may represent one of the cellular mechanisms underlying cholinergic tuning of brain function. [ABSTRACT FROM AUTHOR]

Microglia, the resident innate immune cells of the CNS, are the primary defenders against microbes and critical to CNS remodeling. Dysregulation of microglial behavior can lead to unchecked pro-inflammatory activity and subsequent neurodegeneration. The molecular mechanisms leading to chronic inflammation and microglial dysfunction in neurodegenerative diseases are not well-understood. It is known that patients with Presenilin 2 ( PS2) mutations develop autosomal dominant Alzheimer disease. We have shown that a lack of normal PS2 function is associated with exaggerated microglia pro-inflammatory responses in vitro. To identify pathways by which PS2 regulates microglia and determine how PS2 dysfunction may lead to altered inflammatory pathways, we pursued an unbiased array approach to assess differential expression of micro RNAs between murine PS2 knockout ( KO) and wild-type microglia. We identified miR146, a negative regulator of monocyte pro-inflammatory response, as constitutively down-regulated in PS2 KO microglia. Consistent with a state of miR146 suppression, we found that PS2 KO microglia express higher levels of the miR146 target protein interleukin-1 receptor-associated kinase-1, and have increased NFκB transcriptional activity. We hypothesize that PS2 impacts microglial responses through modulation of miR146a. PS2 dysfunction, through aging or mutation, may contribute to neurodegeneration by influencing the pro-inflammatory behavior of microglia. [ABSTRACT FROM AUTHOR]

Peptide hormones synthesized by secretory neurons in the CNS are important regulators of physiology, behavior, and development. Like other neuropeptides, they are synthesized from larger precursor molecules by a specific set of enzymes. Using a combination of neurogenetics, immunostainings, and direct mass spectrometric profiling, we show that the presence of Drosophila prohormone convertase 2 encoded by the gene amontillado (amon) is a prerequisite for the proper processing of neuropeptide hormones from the major neurohemal organs of the CNS. A loss of amon correlates with a loss of neuropeptide hormone signals from the larval ring gland and perisympathetic organs. Neuropeptide hormone signals were still detectable in the adult corpora cardiaca of older amon-deficient flies which were amon heat-shock-rescued until eclosion. A semiquantification by direct peptide profiling using stable isotopic standards showed, however, that their neuropeptide hormone levels are strongly reduced. Targeted expression of GFP under the control of amon regulatory regions revealed a co-localization with the investigated peptide hormones in secretory neurons of the brain and ventral nerve cord. The lack of AMON activity resulted in a deficiency of L3 larva to enter the wandering phase. In conclusion, our findings provide the first direct evidence that AMON is a key enzyme in the production of neuropeptides in the fruitfly. [ABSTRACT FROM AUTHOR]

The article presents a research study regarding the characterization of cultures formed by the re-aggregation of dissociated postnatal central nervous system tissue. These cultures, known as Hi-Spots, have properties of complex neuronal networks and are insensitive to glutamate toxicity, which allows for detailed functional analyses which can reduce the need for in vivo experiments.

The article presents a research study over neuronal activation in the Central Nervous System after ozone inhalation using Fos straining in adult rats. The author explains the mechanism through which ozone causes lung inflammation, inducing the activation of neurons of the nucleus tractus solitarius as well as stress responsive neurons of the central nervous system.

The article discusses the relevance of cellular membrane domains in the physiology and pathology of central nervous system (CNS). It states that cellular membrane has a complex and functional role in CNS including neuronal population differentiation, migration of immature precursors in the CNS, and creation and maintenance of myelin organization. It also mentions the fourth International Society for Neurochemistry (ISN) Special Neurochemistry Conference held in Sicily, Italy on May 22-26, 2010.