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Sökning: WFRF:(Forloni Gianluigi)

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1.
  • Ferrari, Raffaele, et al. (författare)
  • Frontotemporal dementia and its subtypes: a genome-wide association study.
  • 2014
  • Ingår i: Lancet Neurology. - 1474-4465. ; 13:7, s. 686-699
  • Tidskriftsartikel (refereegranskat)abstract
    • Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.
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2.
  • Svensson, Christina, 1971- (författare)
  • Altered cell signaling linked to neurodegeneration : Studies on scrapie-infected neuroblastoma cells and activated microglia
  • 2011
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Prion diseases are neurodegenerative disorders that can affect humans and animals. The underlying event is a conformational change of the normal cellular prion protein (PrPC) into an aberrant isoform termed PrP-scrapie (PrPSc). PrPSc is thought to lead to neurodegeneration and activation of glial cells. Scrapie infection of neuroblastoma cells was shown to increase the expression of insulin receptor (IR). Additionally, a marked reduction of 125I-insulin binding sites was observed. Insulin stimulation showed alteration in both IR β-subunit tyrosine phosphorylation and extracellular signal regulated kinase-2 (ERK2) activity.  Furthermore, scrapie infection was shown to increase insulin-like growth factor-1(IGF-1) receptor (IGF-1R) expression, although the number of 125I-IGF-1-binding sites was reduced. Also binding affinity of 125I-IGF-1 to its receptor was reduced, and tyrosine phosphorylation of IGF-1R-β-subunit in response to IGF-1 was altered. The increased levels of neurotrophic receptors might represent a neuroprotective response to prion infection. However, scrapie infection instead leads to decreased function, decreased levels of functional receptors, or both, which could promote neurodegeneration in prion diseases, through attenuated neurotrophic support. In BV-2 microglial cells, LPS-induced iNOS (inducible nitric oxide synthase) expression and subsequent NO production were mainly mediated through c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathway. Antioxidant treatment indicates that oxidative suppressing mechanism(s) acts on JNK pathway possibly as a regulatory mechanism controlling the NO levels. The JNK pathway was also shown to play an important role in the survival of BV-2 cells. We show that BV-2 cells are protected from ongoing apoptosis by pro-survival activity mediated both by the JNK and p38 MAPK pathway during LPS-induced inflammation. This is very interesting findings since it is important for microglia to respond properly to a pathogen, without themselves being affected and undergo apoptosis.
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3.
  • Tehranian, Roya, 1969- (författare)
  • On inflammatory cytokines and β-amyloid peptides in acute and chronic neurodegeneration
  • 2001
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Insults to the brain as well as neurodegenerative diseases are known to elicit inflammatory responses. Inflammation in the brain can on one hand initiate processes that are harmful to the injured tissue and exacerbate the damage, leading to neuronal degeneration and glial activation, and on the other hand activate processes that may be necessary for repair mechanisms and regeneration. Among the mediators of inflammatory response in the brain are the inflammatory cytokines. The most studied are interleukin-1 (IL)-1, IL-6 and tumor necrosis factor-alfa (TNF- ). Although the expression of these cytokines is low under normal conditions in the brain, it can be rapidly induced in response to injury.This thesis is focused on the role of IL-1 family of proteins, namely the agonists IL-1 and and the endogenous IL-1 receptor antagonist (IL-1ra), and IL-6, in different experimental models of neurodegeneration. In order to study the role of IL-1 family of proteins during inflammation in an excitotoxic model of brain injury, adult rats were injected systemically with kainic acid, a glutamate analogue known to evoke seizures and neuronal cell loss in the rat brain. Using the combined technique of reverse-transcriptase coupled to PCR (RT-PCR) and in situ hybridization histochemistry, an upregulation of microglial mRNA expression of IL-1 and IL-1ra was found in brain areas with neuronal degeneration, such as the hippocampus and amygdala. IL-1ra mRNA was induced at later time point than IL-1 mRNA and was identified as the transcript coding for the secreted isoform of IL-1ra. This suggets that upregulation of these cytokines is a part of an inflammtory response associated with neurodegeneration and that the effect of IL-1 may be regulated by the expression of IL-1ra in this model. In order to study the role played by IL-1 in inflammation associated with traumatic brain injury (TBI), an experimental model was inflicted on transgenic mice. Heterozygous overexpression of the human secreted isoform of IL-1ra in the brain decreased the induction of IL-1 and IL-6 after injury. Using a neurological severity score (NSS), which mainly reflects motor recovery, we found that these animals recovered faster as compared to their non-transgenic littermates.Furthermore, the proinflammatory cytokine expression was studied by RT-PCR in a mouse model of Alzheimer's disease (AD). The Tg2576 mice strain overexpress -amyloid (A ) precursor protein with the "Swedish" mutation linked to familiar AD and exhibits some of the neuropathology associated with AD, such as the deposition of insoluble extracellular amyloid fibrils (amyloid plaques) in specific brain regions. Analysis of expression of cytokines in the brain of Tg2576 mice revealed an early induction of IL-6 in the hippocampus and cerebral cortex that precedes the formation of amyloid plaques. This finding is interesting since in AD brain IL-6 is detected in microglia in the vicinity of diffuse plaques (non-fibrillar). Thus, the result from this study suggests that increased IL-6 expression may be an early event in AD inflammation.The main constituent of amyloid plaques in the AD brain is the A peptide. The synthetic peptide A (25-35), a neurotoxic fragment of the full-length A peptide was studied for its ability to activate glial cells in culture and induce cytokine expression, as well as for its influence on G-protein coupled signalling in rat brain tissue. A (25-35) treatment of mixed astroglial cultures resulted in marked induction of IL-6 mRNA as studied by RT-PCR. Together with the results from the Tg2576 mice these results suggest a role for IL-6 in AD pathogenesis.Alteration in cellular signal transduction has also been reported in AD brain. A (25-35) was shown to stimulate the enzymatic activities of GTPase and adenylate cyclase in membrane preparations from rat hippocampus and cerebral cortex, which are particularly affected regions in AD brain. Using Pertussis toxin treated membranes, the stimulatory effect on GTPase activity was totally abolished, suggesting that Gi/Go type of G-proteins mediated the effect of the A peptide. 
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