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| 3. |
- Dehghani, F., et al.
(författare)
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Inhibition of microglial and astrocytic inflammatory responses by the immunosuppressant mycophenolate mofetil
- 2010
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 36:7, s. 598-611
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Nucleotide depletion induced by the immunosuppressant mycophenolate mofetil (MMF) has been shown to exert neuroprotective effects. It remains unclear whether nucleotide depletion directly counteracts neuronal demise or whether it inhibits microglial or astrocytic activation, thereby resulting in indirect neuroprotection. Methods: Effects of MMF on isolated microglial cells, astrocyte/microglial cell co-cultures and isolated hippocampal neurones were analysed by immunocytochemistry, quantitative morphometry, and elisa. Results: We found that: (i) MMF suppressed lipopolysaccharide-induced microglial secretion of interleukin-1 beta, tumour necrosis factor-alpha and nitric oxide; (ii) MMF suppressed lipopolysaccharide-induced astrocytic production of tumour necrosis factor-alpha but not of nitric oxide; (iii) MMF strongly inhibited proliferation of both microglial cells and astrocytes; (iv) MMF did not protect isolated hippocampal neurones from excitotoxic injury; and (v) effects of MMF on glial cells were reversed after treatment with guanosine. Conclusions: Nucleotide depletion induced by MMF inhibits microglial and astrocytic activation. Microglial and astrocytic proliferation is suppressed by MMF-induced inhibition of the salvage pathway enzyme inosine monophosphate dehydrogenase. The previously observed neuroprotection after MMF treatment seems to be indirectly mediated, making this compound an interesting immunosuppressant in the treatment of acute central nervous system lesions.
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| 4. |
- Hong, Xu, et al.
(författare)
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Memory deficits correlate with tau and spine pathology in P301S MAPT transgenic mice.
- 2014
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 40:7, s. 833-843
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Tidskriftsartikel (refereegranskat)abstract
- AIM: P301SMAPT transgenic mice (P301S mice) are a widely used model of frontotemporal dementia and parkinsonism linked to chromosome 17 with tau pathology (FTDP-17-tau). However, a systematic correlation between cognitive deficits and cellular tau pathology at different ages is still missing. Therefore, our study investigated memory deficits of P301S mice in relation to pathological tau species and dendritic spine pathology throughout adulthood. METHODS: We analysed P301S mice behaviourally with the novel open field, rotarod, and Morris water maze tests to measure deficits in locomotion, balance and cognition, respectively; immunohistochemically with different tau antibodies for specific tau species; and with Golgi staining for dendritic spine pathology. RESULTS: We confirmed the occurrence of locomotor deficits at an age of 5months and newly report memory deficits from 2.5months of age onwards. At this early age, MC1 and CP13, but not AT180 immunoreactivity, was prominent in the hippocampus of P301S mice. Neuronal cell loss in the hippocampus of P301S mice was not observed to occur till 6months of age. However, there was a significant reduction in the density of dendritic spines from young adulthood onwards in hippocampal pyramidal neurones. CONCLUSION: In P301S mice, memory deficits precede the onset of locomotor dysfunction and coincide with the appearance of conformationally changed, S202-phosphorylated tau and reduced spine density in the absence of neuronal cell loss in the hippocampus. Our finding provides insights into the toxic effects of different tau species in vivo and may facilitate the development of new therapies against neurodegenerative tauopathies. © 2014 British Neuropathological Society.
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- Kovacs, Gabor G, et al.
(författare)
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Neuropathology of the hippocampus in FTLD-Tau with Pick bodies : A study of the BrainNet Europe Consortium
- 2013
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 39:2, s. 166-178
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Frontotemporal lobar degeneration with Pick bodies (Pick's disease) is characterized by the presence of tau immunoreactive spherical structures in the cytoplasm of neurons. In view of confusion about the molecular pathology of Pick's disease, we aimed to evaluate the spectrum of tau pathology and concomitant neurodegeneration-associated protein depositions in the characteristically affected hippocampus. Methods: We evaluated immunoreactivity for tau (AT8, 3R, 4R), α-synuclein, TDP43, p62, and ubiquitin in the hippocampus, entorhinal and temporal cortex in 66 archival cases diagnosed neuropathologically as Pick's disease. Results: Mean age at death was 68.2 years (range 49 to 96). Fifty-two (79%) brains showed 3R immunoreactive spherical inclusions in the granule cells of the dentate gyrus. These typical cases presented mainly with the behavioural variant of FTD, followed by progressive aphasia, mixed syndromes or early memory disturbance. α-Synuclein immunoreactivity was seen only in occasional spherical tau-positive inclusions, TDP-43 IR was absent, and 4R IR was present only as neurofibrillary tangles in pyramidal neurons. Aβ immunoreactivity was observed in 16 cases; however, the overall level of Alzheimer's disease-related alterations was mainly low or intermediate (n = 3). Furthermore, we identified six cases with unclassifiable tauopathy. Conclusions: 1) Pick's disease may occur also in elderly patients and is characterized by a relatively uniform pathology with 3R tau inclusions particularly in the granule cells of dentate gyrus; 2) even minor deviation from these morphological criteria suggests a different disorder; and 3) immunohistological revision of archival cases expands the spectrum of tauopathies that require further classification.
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- Leinonen, Ville, et al.
(författare)
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Post-mortem findings in 10 patients with presumed normal pressure hydrocephalus and review of the literature
- 2011
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 38:1, s. 72-86
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Neuropathological features of idiopathic normal pressure hydrocephalus (iNPH) are poorly characterized. Brain biopsy during life may help in the differential diagnosis of dementia but post-mortem validation of biopsy findings is scarce. Here we review and report brain biopsy and post-mortem neuropathological findings in patients with presumed NPH. Methods: We evaluated 10 patients initially investigated by intraventricular pressure monitoring and a frontal cortical biopsy for histological and immunohistochemical assessment as a diagnostic procedure for presumed NPH. Results: Out of the 10 patients, eight were shunted and seven benefited. Until death, six had developed severe and two mild cognitive impairment. One was cognitively unimpaired, and one was mentally retarded. Three subjects displayed Ab aggregates in their frontal cortical biopsy obtained at the initial procedure. One of these patients developed Alzheimer's disease during a follow-up time of nearly 10 years. One patient with cognitive impairment and NPH suffered from corticobasal degeneration. In six patients various vascular lesions were seen at the final neuropathological investigation. Five of them were cognitively impaired, and in four vascular lesions were seen sufficient in extent to be considered as causative regarding their symptoms. Conclusions: The frequent finding of vascular pathology in NPH is intriguing suggesting that vascular alterations might be causative of cognitive impairment in a notable number of patients with NPH and dementia. Brain biopsy can be used to detect Ab aggregates but neuropathological characteristics of iNPH as a distinct disease still need to be discovered.
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| 7. |
- Martikainen, P., et al.
(författare)
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Brain pathology in three subjects from the same pedigree with presenilin-1 (PSEN1) P264L mutation
- 2010
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 36:1, s. 41-54
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Our goal was to assess pathological lesions with respect to type and distribution and to compare these results with the clinical presentation including symptoms and mode of progression in three members of the same pedigree with a P264L presenilin-1 gene mutation. METHODS: We used immunohistochemistry and a tissue microarray technique applied to post mortem brain tissue samples. RESULTS: All three subjects were demented, one subject displayed spastic paraparesis and two had Parkinsonism. All three cases displayed abundant cotton wool plaques composed of amyloid-beta42 but also containing other proteins, for example, hyperphosphorylated tau and in one case TAR DNA binding protein 43. The distribution of the pathology varied and seemed to some extent to be related to the clinical phenotype. An association was detected between neocortical/thalamic involvement and psychiatric symptoms, between striatal/amygdaloid involvement and Parkinsonism, and between brainstem involvement and spastic paraparesis. CONCLUSIONS: Subjects from the same pedigree carrying the same mutation display a clear variability in the type and distribution of pathology as well as in their clinical symptoms. These results emphasize that still unknown factors significantly alter the pathological and clinical phenotypes in genetically predetermined disease.
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| 8. |
- Petit, Géraldine, et al.
(författare)
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Review: The future of cell therapies and brain repair: Parkinson's disease leads the way.
- 2014
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Ingår i: Neuropathology & Applied Neurobiology. - : Wiley. - 1365-2990 .- 0305-1846. ; 40:1, s. 60-70
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Forskningsöversikt (refereegranskat)abstract
- During the past 40 years brain tissue grafting techniques have been used both to study fundamental neurobiological questions and to treat neurological diseases. Motor symptoms of Parkinson's disease are largely due to degeneration of midbrain dopamine neurones. Because the nigrostriatal pathology is relatively focused anatomically, Parkinson's disease is considered the ideal candidate for brain repair by neural grafting and dopamine neurone transplantation for it has led the way in the neural transplantation research field. In this mini-review, we briefly highlight four important areas of development. First, we describe marked functional benefits up to 18 years after transplantation surgery in patients with Parkinson's disease. This is proof-of-principle that, using optimal techniques and patient selection, grafted dopamine neurones can work in humans and the duration of the benefit exceeds placebo effects associated with surgery. Second, we describe that eventually protein aggregates containing α-synuclein, identical to Lewy bodies, develop inside foetal dopamine neurones transplanted to patients with Parkinson's disease. This gives clues about pathogenetic mechanisms operating in Parkinson's disease, and also raises the question whether neural graft function will eventually decline as the result of the disease process. Third, we describe new emerging sources of transplantable dopamine neurones derived from pluripotent stem cells or reprogrammed adult somatic cells. Fourth, we highlight an important European Union-funded multicentre clinical trial involving transplantation of foetal dopamine neurones in Parkinson's disease. We describe the design of this ongoing trial and how it can impact on the overall future of cell therapy in Parkinson's disease.
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| 9. |
- Qu, Mingqi, et al.
(författare)
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Molecular Genetic and Epigenetic analysis of NCX2/SLC8A2 at 19q13.3 in Human Gliomas
- 2010
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 36:3, s. 198-210
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Tidskriftsartikel (refereegranskat)abstract
- AimLoss of heterozygosity (LOH) at 19q13.3 is a common genetic change in human gliomas, indicating yet unknown glial-specific tumour suppressor genes in this chromosome region. NCX2/SLC8A2 located on chromosome 19q13.32 encodes a Na(+)/Ca(2+)exchanger, which contributes to intracellular Ca(2+)homeostasis. Its expression is restricted to brain, and it is neither present in other normal tissues nor in gliomas at any significant level. The aim of this study was to investigate if NCX2 might be a tumour suppressor gene involved in glioma.MethodsWe performed a systematic analysis of NCX2 in 42 human gliomas using microsatellite analysis for evaluation of LOH at 19q, DNA sequencing and DNA methylation analysis.ResultsExcept for three known intragenic SNPs, rs12459087, rs7259674, and rs8104926, no NCX2 sequence variations were detected in any of the tumour samples. Furthermore, a CpG island in the 5' promoter region of NCX2 was unmethylated. Interestingly, the CpG sites of three gene-body CpG islands located in exon 2, intron 2-3 and exon 3 and of a 5' CpG rich area relevant to so called CpG island shore of NCX2 were methylated in all 8 glioma samples and in 3 established glioma cell lines tested. Surprisingly, NCX2 could be activated by addition of the DNA methylation inhibitor 5-aza-2'-deoxycytidine to glioma cell lines in which NCX2 was completely silent.ConclusionResults indicate that DNA methylation may play a key role in the transcriptional silencing of NCX2.
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| 10. |
- Santillo, Alexander Frizell, et al.
(författare)
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Von Economo neurons are selectively targeted in frontotemporal dementia.
- 2013
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Ingår i: Neuropathology & Applied Neurobiology. - : Wiley. - 1365-2990 .- 0305-1846. ; 39:5, s. 572-579
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Tidskriftsartikel (refereegranskat)abstract
- Von Economo neurons (VEN) are bipolar neurons located in the anterior cingulate cortex (ACC) and the frontoinsular cortex (FI), areas affected early in behavioural variant frontotemporal dementia (bvFTD), in which VEN may constitute a selectively vulnerable cellular population. Aim A previous study has shown a selective loss of VEN in FTD above other neurons in the ACC of FTD. The aim of this study was to confirm this finding in a larger cohort, using a different methodology, and to examine VEN loss in relation to neuropathological severity and molecular pathology. Methods VEN and neighbouring neurons (NN) were quantified in layer Va and Vb of the right dorsal anterior cingulate cortex in 21 cases of behavioural variant FTD, 10 cases of Alzheimer's disease (AD) and 10 non-demented controls (NDC). Results A marked VEN reduction was seen in all FTD cases. In the neuropathologically early cases of FTD (n=13), VEN/10000 NN was significantly reduced by 53 % compared with NDC (p<0.001) and 41% compared with AD (p=0.019), whereas AD patients showed a non-significant 30% reduction of VEN/10000 NN compared with NDC. VEN reduction was present in all protein pathology subgroups. Discussion In conclusion, this study confirms selective sensitivity of VEN in FTD and suggests that VEN loss is an early event in the neurodegenerative process.
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| 11. |
- Sikkema, A. H., et al.
(författare)
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Vascular endothelial growth factor receptor 2 (VEGFR-2) signalling activity in paediatric pilocytic astrocytoma is restricted to tumour endothelial cells
- 2011
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 37:5, s. 538-548
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Tumours depend on angiogenesis for enhanced tumour cell survival and progression. Vascular endothelial growth factor receptor (VEGFR) signalling plays a major part in this process. Previously, we evaluated tyrosine kinase activity in paediatric brain tumour tissue lysates using a peptide microarray containing 144 different tyrosine kinase peptide substrates. When applied to paediatric pilocytic astrocytoma tissue, this analysis revealed extensive phosphorylation of VEGFR-derived peptides. The aim of the current study was to validate this result and determine the presence of VEGFR-2 activity in paediatric pilocytic astrocytoma as the main VEGFR in terms of mitogenic signalling. In addition, the localization of VEGFR1-3 mRNA expression was assessed. Methods: VEGFR-2 phosphorylation was determined by adopting a proximity ligation assay approach. Enrichment of endothelial markers and VEGFRs in tumour endothelium was determined by quantitative polymerase chain reaction (qPCR) analysis of laser-microdissected blood vessels. Results: Proximity ligation assays on tumour cryosections showed the presence of phosphorylation of VEGFR-2, which primarily localized to vascular endothelium. qPCR analysis of endothelial markers and VEGFRs showed a 13.6-fold average enrichment of VEGFR-2 expression in the laser-microdissected endothelium compared to whole tumour. Also the expression of VEGFR-1 and -3 was highly enriched in the endothelium fraction with an average fold-enrichment of 16.5 and 50.8 respectively. Conclusions: Phosphorylated VEGFR-2 is detected on endothelial cells in paediatric pilocytic astrocytoma. Furthermore, endothelial cells are the main source of VEGFR1-3 mRNA expression. This suggests a crucial role for VEGF/VEGFR-induced angiogenesis in the progression and maintenance of these tumours.
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