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Inger Nennesmo

Publications and source records attributed to Inger Nennesmo.

17 recordsLinked to original sources
PubMed2006

Apolipoprotein E deficiency increased microglial activation/CCR3 expression and hippocampal damage in kainic acid exposed mice.

Apolipoprotein E (apoE) down-regulates microglial activation and the secretion of inflammatory molecules in an isoform specific fashion (E2 > E3 > E4); the E4 isoform is over-represented in Alzheimer cases while E2 is under-represented. To better define the role of apoE in neurodegeneration, we contrasted apoE knockout (n = 38) and wild-type mice (n = 41) with respect to seizure activity, mortality, locomotion, hippocampal microglial activation/chemokine receptor expression, and damage to the hippocampus after nasal administration of kainic acid (KA) (water as controls). Mice lacking apoE demonstrated more hunching and less rearing, more damage to neurons in the CA3 region (mean histopathologic score: 3.7 vs. 1.6, p < 0.05), greater microglial activation confirmed by high levels of CD11b and CD86 expression in hippocampus (CD11b p < 0.01, CD86 p < 0.05), and a greater percentage of activated microglia expressing CC chemokine receptors 3 (CCR3) (p < 0.05). Taken together, these findings imply that apoE modulates hippocampal damage induced by KA and found early in the sequence of human Alzheimer's brain changes, by modulating microglial activation.

Analysis of Variance↗
PubMed2006

POLG1 mutations associated with progressive encephalopathy in childhood.

We have identified compound heterozygous missense mutations in POLG1, encoding the mitochondrial DNA polymerase gamma (Pol gamma), in 7 children with progressive encephalopathy from 5 unrelated families. The clinical features in 6 of the children included psychomotor regression, refractory seizures, stroke-like episodes, hepatopathy, and ataxia compatible with Alpers-Huttenlocher syndrome. Three families harbored a previously reported A467T substitution, which was found in compound with the earlier described G848S or the W748S substitution or a novel R574W substitution. Two families harbored the W748S change in compound with either of 2 novel mutations predicted to give an R232H or M1163R substitution. Muscle morphology showed mitochondrial myopathy with cytochrome c oxidase (COX)-deficient fibers in 4 patients. mtDNA analyses in muscle tissue revealed mtDNA depletion in 3 of the children and mtDNA deletions in the 2 sibling pairs. Neuropathologic investigation in 3 children revealed widespread cortical degeneration with gliosis and subcortical neuronal loss, especially in the thalamus, whereas there were only subcortical neurodegenerative findings in another child. The results support the concept that deletions as well as depletion of mtDNA are involved in the pathogenesis of Alpers-Huttenlocher syndrome and add 3 new POLG1 mutations associated with an early-onset neurodegenerative disease.

Adolescent↗
PubMed2005

Increased microglial activation and astrogliosis after intranasal administration of kainic acid in C57BL/6 mice.

Glutamate excitotoxicity plays a key role in inducing neuronal cell death in many neurological diseases. In mice, intranasal administration of kainic acid (KA), an analogue of the excitotoxin glutamate, results in hippocampal cell death and provides a well-characterized model for studies of human neurodegenerative diseases. In this study, we describe neurodegeneration and gliosis following intranasal administration of KA in C57BL/6 mice. By using Nissl's staining, neurodegeneration was found in area CA3 of hippocampus, and neuronal apoptosis was demonstrated by enhanced FAS(CD95/APO-1) expression detected by immunohistochemistry and Western blotting. Astrogliosis was exhibited by increased glial fibrillary acidic protein (GFAP) expression in the hippocampus and cortex. We also studied the profile of molecular expression on microglia in C57BL/6 mice. One and 3 days after KA administration, CD45, F4/80, CD86, MHCII, iNOS but not CD40 expression was enhanced or induced on microglia. In summary, KA administration results in an early microglial activation and a prolonged astrogliosis in C57BL/6 mice.

Animals↗
PubMed2005

Human monoclonal antibodies against amyloid-beta from healthy adults.

Two anti-amyloid-beta human antibody-producing cell lines were established from amyloid-beta (Abeta)-selected lymphocytes from peripheral blood of healthy adults. ELISA and Western blot analysis showed that the monoclonal antibodies bound with high affinity to the 43 amino acid-long amyloid-beta peptide. The antigen epitope of these antibodies encountered within amino acids 1-16 of the amyloid-beta peptide. The antibodies did not bind to several immunoglobulin light chain amyloids (AL) and amylin. One of the monoclonals was tested by immunohistochemistry for the binding to frozen sections of brains derived from patients with Alzheimer's disease. It specifically and intensively stained diffuse and core amyloid-beta plaques; whereas, sections from normal brains were not stained. Concomitant staining with a commercial mouse anti-amyloid-beta monoclonal antibody co-localized with that of the human antibody. Simultaneous staining with the human antibody and Congo red implied that the antibody binds primarily to an early immature form of beta-amyloid. Human monoclonal antibodies, which resemble physiologically normal non-pathogenic and possibly protective antibodies in healthy adults, might be attractive candidates for immune therapy of Alzheimer's disease.

Adult↗
PubMed2004

Vascular endothelial growth factor prolongs survival in a transgenic mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with the death of motor neurons in the spinal cord and brainstem. The cause of ALS is unknown and there is no cure. This study demonstrates, for the first time, that vascular endothelial growth factor (VEGF) delays progression of symptoms and prolongs survival in a Cu/Zn superoxide dismutase (SOD1) transgenic mouse model of ALS. These observations suggest that VEGF or related compounds, might be of value in the treatment of ALS patients.

Age Factors↗
PubMed2004

Familial insensitivity to pain (HSAN V) and a mutation in the NGFB gene. A neurophysiological and pathological study.

We have studied a large Swedish family with a mutation in the nerve growth factor beta (NGFB) gene causing insensitivity to deep pain without anhidrosis (hereditary sensory and autonomic neuropathy, type V; HSAN V). Painfree joint destruction and fractures were common. Peripheral nerve conduction was normal, but temperature thresholds were increased. Sural nerve biopsies showed a moderate loss of A delta fibers and a severe reduction of C fibers. The three most severely affected cases were all born to consanguineous parents, and were homozygotes for the causal genetic mutation. Treatment of these patients is discussed.

Adult↗
PubMed2004

Anti-cytokine autoantibodies in experimental autoimmune neuritis in Lewis rats.

Experimental autoimmune neuritis (EAN) is a CD4+ T-cell-mediated, inflammatory demyelinating disease of the peripheral nervous system (PNS) that serves as a model for Guillain-Barre syndrome (GBS) in humans. Cytokine production has been suggested to act a pathogenic role for EAN. To study the potential role of cytokines in context with cytokine autoantibodies (Aabs) in EAN, we used in situ hybridization to detect mRNA expression of interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, IL-4, IL-10, and transforming growth factor (TGF)-beta in lymph node mononuclear cell (MNC) and in sciatic nerve sections, as well as ELISA for detection of their autoantibodies in sera and cerebrospinal fluid (CSF) over the course of EAN. Increased mRNA expression for IFN-gamma and TNF-alpha was registered correlating with the peak of clinical signs of EAN, and high levels of mRNA expression for IL-4, IL-10, and TGF-beta were associated with EAN recovery. The levels of cytokine mRNAs were generally inversely correlated to their autoantibodies in serum and CSF, whereby the CSF levels were equal to or lower than the serum levels. Autoantibodies to IFN-gamma dose-dependently inhibited IFN-gamma-induced MHC expression by peritoneal macrophages proving a neutralizing biological effect of these autoantibodies. Our data demonstrate the existence of the anti-cytokine autoantibodies in the sera and CSF of rats with EAN; however, the role of anti-cytokine autoantibodies in the disease process of EAN remains to be resolved.

Animals↗
PubMed2004

CCR5 deficiency does not prevent P0 peptide 180-199 immunized mice from experimental autoimmune neuritis.

Experimental autoimmune neuritis (EAN) is an inflammatory autoimmune demyelinating disease of peripheral nervous system (PNS) and represents an animal model of Guillain-Barré syndrome (GBS) in man. The inflammatory cell infiltrating into the PNS is a prerequisite for developing EAN. To explore the role of CC chemokine receptor 5 (CCR5) in the inflammatory process of EAN, we induced EAN in CCR5-deficient (CCR5(-/-)) mice with P0 protein peptide 180-199. We found that CCR5(-/-) mice showed a similar EAN clinical course and severity as well as profile of infiltrating macrophages and T cells in cauda equina (CE) of EAN and the same levels of spleen mononuclear cell (MNC) response to antigen and mitogen when compared with CCR5(+/+) control mice. However, increased IP-10 and MIP-1beta production in sciatic nerves were seen in CCR5(-/-) mice. These results suggest that CCR5 deficiency does not prevent P0 peptide 180-199-immunized mice from EAN. Increased MIP-1beta and IP-10 in sciatic nerves may compensate the CCR5 deficiency and contribute to inflammatory cells infiltrating to the PNS.

Animals↗
PubMed2004

Increased susceptibility to experimental autoimmune neuritis after upregulation of the autoreactive T cell response to peripheral myelin antigen in apolipoprotein E-deficient mice.

Experimental autoimmune neuritis (EAN), an acute demyelinating inflammatory disease of the peripheral nervous system (PNS), is a good model for the human counterpart, Guillain-Barré syndrome. Apolipoprotein E (ApoE), a 34 kDa glycosylated protein with multiple biological properties, has been linked both with the innate immune response of mice and with neurological disease. The present study investigated the previously unexplored role of ApoE in autoimmune-mediated demyelination. ApoE-deficient (apoE -/-) mice exhibited a greater susceptibility to EAN induced by the PNS myelin P0 protein peptide 180-199, as compared to wild type (apoE +/+) mice. The augmented susceptibility seen in apoE -/- mice was associated with increased inflammatory cell infiltrates in the PNS during the effector phase. Although the 2 groups of mice exhibited no quantitative or proportional differences in splenic lymphocyte populations, the apoE -/- mice showed enhanced antigen-specific proliferation of T cells of spleen, which is related to modified macrophage function, upregulation of Th1 and downregulation of Th2-autoreactive responses to P0 peptide. These effects were shown as increased numbers of IFN-gamma expressing cells in the spleen and of IFN-gamma, IL-12 and TNF-alpha expressing cells in the PNS, as well as a decreased IL-10 production by splenic cells in apoE -/- mice. In addition, apoE -/- mice had enhanced antigen-specific antibody responses, which might have contributed to their aggravated EAN. These data provide strong evidence that apoE acts as an inhibitor of this inflammatory and demyelinating disease by upregulating IL-10, as well as by inhibiting Th1 responses and antigen-specific antibody formation. These data may aid the development of new and more effective therapeutic strategies for inflammatory and demyelinating diseases such as Guillain-Barré syndrome.

Analysis of Variance↗
PubMed2003

CBA/J mice infected with Trypanosoma cruzi: an experimental model for inflammatory myopathies.

Idiopathic inflammatory myopathies are inflammatory disorders of unknown origin, characterized by muscle weakness. The aim of our study was to establish and characterize an animal model for chronic inflammatory myopathy which would permit investigations of the role of T-cells in chronic myositis as well as of the mechanisms for muscle weakness in chronic inflammatory muscle disorders. CBA/J mice were infected with the protozoan parasite Trypanosoma cruzi. Immunohistochemistry was used to characterize the distribution and composition of inflammatory infiltrates, and demonstrated a chronic focal inflammation comprised mainly of T-cells and macrophages in infected mice. The inflammatory infiltrates were predominantly found in the endomysium and, to a lesser extent, in perivascular areas. CD8(+) T-cells were found to have invaded nonnecrotic muscle fibers. Degenerating muscle fibers were also found, as well as an increased number of central muscle nuclei. The murine model described in this article may be useful in studying certain aspects of idiopathic inflammatory myopathies such as the role of T-cells in chronic muscle inflammation and chronic myocytotoxicity.

Animals↗
PubMed2003

Alterations of mitochondrial function and correlations with personality traits in selected major depressive disorder patients.

BACKGROUND: Increased occurrence of several physical conditions has been reported in patients with depressive disorders. Various physical conditions and depressive disorder have been reported in patients with mitochondrial disorders. The aim of this study was to investigate mitochondrial function in selected depressed patients in search of an aetiological or pathophysiological factor common to both depression and physical symptoms. METHODS: Muscle biopsy was performed in 28 patients with a lifetime prevalence of major depressive disorder (MDD), and at least three chronic physical conditions that have been reported to be common in depressive as well as in mitochondrial disorders. Morphologic and biochemical investigations including mitochondrial ATP production rate (MAPR) by the bioluminometric method, spectrophotometric analyses of mitochondrial enzymes, and long-PCR and Southern blot techniques to detect mitochondrial DNA (mtDNA) deletions were performed. The Karolinska Scales of Personality (KSP) with 15 scales assessing vulnerability to psychopathology was filled in by 21 patients. RESULTS: Decreases of MAPR and enzyme ratios were found in the patients in comparison with controls (P<0.01). Deletions of mtDNA assessed with long-PCR were more frequent in patients than in controls (chi-square test P<0.05). Correlations were found between MAPR and the KSP scales 'Somatic Anxiety', 'Psychasthenia', and 'Suspicion' (P<0.01). LIMITATIONS: Results cannot be compared with previous studies, and cannot be generalized to all MDD patients. Individually matched controls were not available. CONCLUSIONS: The results suggest that mitochondrial dysfunction is associated with vulnerability to psychopathology in this selected patient group.

Adult↗
PubMed2002

Multitracer study with positron emission tomography in Creutzfeldt-Jakob disease.

During the period February 1997 to April 2000, 15 patients with clinical symptoms of Creutzfeldt-Jakob disease (CJD) were referred to Uppsala University PET Centre. Positron emission tomography (PET) was performed to detect characteristic signs of the disease, e.g. neuronal death and/or astrocytosis in the brain. The examinations were performed in one session starting with oxygen-15 labelled water scan to measure regional cerebral blood flow, followed by imaging with the monoamine oxidase B inhibitor N-[(11)C-methyl]- L-deuterodeprenyl (DED) to assess astrocytosis in the brain and finally imaging with fluor-18 2-fluorodeoxyglucose (FDG) to assess regional cerebral glucose metabolism (rCMR(glu)) [corrected]. Nine of the patients fulfilled the clinical criteria of probable CJD. In eight of them, FDG and DED imaging revealed, in comparison with normal controls, a typical pattern characterized by a pronounced regional decrease (<2SD) in glucose brain metabolism, indicative of neuronal dysfunction; this was accompanied by a similar increase (>2SD) in DED binding, indicating astrocytosis. These changes were most pronounced in the cerebellum and the frontal, occipital and parietal cortices, whereas the pons, the thalamus and the putamen were less affected and the temporal cortex appeared unaffected. The cerebral blood flow showed a pattern similar to that observed with FDG. In the ninth patient, analysis with DED was not possible. The diagnosis of definite CJD according to international consensus criteria was confirmed in six of these patients. In one patient with probable CJD, protease-resistant prion protein (PrPres) could not be demonstrated. In two patients with probable CJD, autopsy was not allowed. Computed tomography and magnetic resonance imaging, performed in four and seven of these nine patients respectively, showed unspecific, mainly atrophic changes. In six other patients, the PET examinations gave a different pattern. In three of them, high rCMR(glu) was noticed in parts of the brain, particularly in the temporal lobes and basal ganglia, which could suggest encephalitis. One of the patients had Sjögren's syndrome, one had paraneoplastic limbic encephalitis and the third recovered spontaneously. In the other three patients, the DED binding was normal despite a hypometabolic glucose pattern. In conclusion, the PET findings obtained using DED and FDG paralleled neuropathological findings indicating neuronal dysfunction and astrocytosis, changes that are found in CJD.

Adult↗
PubMed2002

Excitotoxic neurodegeneration induced by intranasal administration of kainic acid in C57BL/6 mice.

Glutamate excitotoxicity plays a key role in inducing neuronal cell death in many neurological diseases. In mice, administration of kainic acid, an analogue of the excitotoxin glutamate, results in hippocampal cell death and seizures. Kainic-acid-induced seizures in mice provide a well-characterized model for studies of human neurodegenerative diseases. However, C57BL/6 mice, which are often used for genetic analyses and transgenic and knockout studies, are resistant to excitotoxicity induced by subcutaneous administration of kainic acid. In the present study, kainic acid administered by the intranasal route was shown to result in continuous tonic-clonic seizures in C57BL/6 mice. These seizures continued for 1-5 h and successfully induced selective lesions in area CA3 of the hippocampus. The survival rate was high even after mice experienced severe seizures. The hippocampal lesions were associated with a high level of cyclooxygenase-2 production as well as astrogliosis. Administration of kainic acid also altered behavioral responses, with mice showing a significant increase in locomotion and rearing activity as indicated by an open-field test. This animal model could provide a valuable tool for exploring the role of excitotoxicity in neuropathological conditions and should be further evaluated in gene-targeting studies of neurodegenerative diseases.

Administration, Intranasal↗
PubMed2002

Interleukin-1alpha expression in capillaries and major histocompatibility complex class I expression in type II muscle fibers from polymyositis and dermatomyositis patients: important pathogenic features independent of inflammatory cell clusters in muscle tissue.

OBJECTIVE: To address the hypothesis that endothelial cells and/or muscle fibers are primary targets in the disease process by analysis of muscle tissue from patients with polymyositis (PM) and dermatomyositis (DM). METHODS: We included patients with laboratory signs and clinical symptoms typical of myositis, but without detectable infiltration of clusters of inflammatory cells in their muscle biopsy samples. An immunohistochemical technique was applied to identify CD3, CD68, lymphocyte function-associated antigen 1alpha, CD11b, very late activation antigen 4, endothelium 4, interleukin-1alpha (IL-1alpha), intercellular adhesion molecule 1, vascular cell adhesion molecule 1, IgG, IgM, IgA, and HLA-A/B/C in muscle tissue. Fiber type was defined by ATPase staining. RESULTS: IL-1alpha expression was detected in endothelial cells of capillaries to a greater extent in patients than in controls, and class I major histocompatibility complex (MHC) expression was significantly increased in muscle fibers. We also observed that class I MHC expression was mainly confined to type II muscle fibers. CONCLUSION: Our findings imply that defined molecular changes of blood vessels and muscle fibers are both independent of adjacent inflammatory infiltrates and could thus be primary events in the development of myositis. Moreover, both IL-1alpha and class I MHC molecules might be important for the development of clinical symptoms in PM and DM patients.

Adult↗
PubMed2002

CD4 and CD8 T cells, but not B cells, are critical to the control of murine experimental autoimmune neuritis.

Experimental autoimmune neuritis (EAN) is a T cell-mediated autoimmune disease of the peripheral nervous system that duplicates the clinical, pathological, and electrophysiological features of Guillain-Barré syndrome in humans. However, the molecular pathogenesis of EAN remains controversial. Therefore, for this study, we induced EAN with P0 protein peptide 180-199 in CD4(-/-), CD8(-/-), CD4(-)8(-), and B cell knockout (microMT) mice to further investigate the roles of these cells in EAN. Our results showed that the severity of clinical signs and histopathological manifestations of EAN and the T cell response to P0 peptide 180-199 in CD4(-/-) mice were significantly lower than those in their wild-type counterparts. CD8(-/-) mice also had a milder clinical course, less histopathological change, and a diminished T cell response to P0 peptide 180-199. However, more severe clinical and histopathological manifestations, a stronger T cell response to P0 peptide 180-199, and enhanced IFN-gamma production in the spleen were observed in the EAN of CD4(-)8(-) and microMT mice, but these were not obviously different from those of wild-type mice. Levels of IgG production were similar in sera from CD4(-/-), CD8(-/-), and CD4(-)8(-), and wild-type mice. These findings suggest that the induction and control of murine EAN are dependent on both CD4(+) and CD8(+) T cells and that B cells apparently do not perpetuate the related inflammatory demyelination.

Animals↗
PubMed2002

Marked heterogeneity of human skeletal muscle lipolysis at rest.

In this study, variations in lipolysis among different muscle groups were examined by measuring local net glycerol release in vivo in healthy, normal-weight subjects (n = 11) during rested, postabsorptive conditions. Microdialysis of the gastrocnemius, deltoid, and vastus lateralis muscle regions revealed that extracellular glycerol concentrations of these three muscle regions were 84.7 +/- 6.7, 59.7 + 7.3, and 56.4 +/- 7.5 micro mol/l, respectively, and the arterial plasma glycerol concentration was 44.8 +/- 2.3 micro mol/l (P = 0.0003-0.006, gastrocnemius vs. others). Local tissue blood flow, as measured by Xe clearance, did not differ among the regions. Net glycerol release was significantly higher in gastrocnemius muscle than in the two other regions. There were no regional differences in glycerol uptake when studied during glycerol infusion. Gastrocnemius muscle showed a dominance of type 1 fibers (70%), whereas the vastus lateralis muscle had equal distribution of fiber types (P = 0.02). No differences in intramuscular triaclyceride content, perimuscular fat, or the adipocyte-specific protein perilipin were observed among the muscle regions. Triglyceride turnover in the gastrocnemius muscle was 3.3 + 1.4% over 24 h, which is about 10 times more rapid than the turnover rate in subcutaneous adipose tissue (P < 0.01). Thus there were marked differences in lipolytic activity among skeletal muscle groups at rest, possibly reflecting variations in fiber type.

Adult↗