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| 3. |
- Andin, Josefine, 1979-, et al.
(författare)
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Influence of environmental enrichment on steady-state mRNA levels for EAAC1, AMPA1 and NMDA2A receptor subunits in rat hippocampus
- 2007
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Ingår i: Brain Research. - : Elsevier BV. - 0006-8993 .- 1872-6240. ; 1174:1, s. 18-27
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Tidskriftsartikel (refereegranskat)abstract
- Interaction with the environment has a key role in refining the neuronal circuitry required for normal brain function throughout life. Profound effects of enriched environment have been shown on neuronal structure and chemistry in experimental animals. Epidemiological studies imply that this is true also in man, thus cognitive stimulation has a protective effect on neurodegeneration, e.g., in Alzheimer's disease. Glutamatergic pathways are imperative for cognitive functions, such as memory, learning and long-term potentiation, and relies on the AMPA and NMDA glutamate receptors and the hippocampus, with its specific subregions, is an important anatomical substrate in this. The glutamate signalling is also dependent on a fine-tuned transport system, in the hippocampus primarily achieved by the glutamate transporter EAAC1. In this study we show how environmental enrichment modulates these parts of the glutamatergic system using quantitative in situ hybridisation. This work demonstrates for the first time that environmental enrichment modulates the mRNA expression of EAAC1 which is significantly and region specifically decreased in the hippocampus. We also provide evidence for regional and hemisphere-specific upregulation of NMDA mRNA in the hippocampus after environmental enrichment. The current work also shows that AMPA mRNA of the hippocampus is not per se changed by environmental enrichment in adult animals. Taken together, our results extend the knowledge of the glutamatergic system of specific regions of the hippocampus and its modulation by environmental enrichment and could contribute to the development of strategies aimed at limiting pathological changes associated with glutamatergic dysfunctions. © 2007.
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- Andin, Josefine, 1979-, et al.
(författare)
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Rivastigmine as a Modulator of the Neuronal Glutamate Transporter rEAAC1 mRNA Expression
- 2005
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Ingår i: Dementia and Geriatric Cognitive Disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 19:1, s. 18-23
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease is a neurodegenerative disorder that affects the cholinergic, glutamatergic and monoaminergic systems in the neocortex and hippocampus. Today, the major pharmacological treatment involves the use of acetylcholinesterase inhibitors (AChEIs). In this study, an in situ hybridisation technique (using digoxigenin-labelled cRNA probes) was used to elucidate changes in mRNA expression of the neuronal glutamate transporter, rat excitatory amino carrier 1 (rEAAC1), after treatment with the AChEI rivastigmine. Compared with saline-treated rats, the rats subchronically (3 days) and chronically (21 days), but not acutely, treated with rivastigmine showed a significant increase in rEAAC1 mRNA expression in the hippocampal areas cornu anterior 1 (CA1), CA2, CA3 and dentate gyrus (p < 0.01), but not in the cortical areas. These results provide the first evidence that the glutamatergic system is modulated following acetylcholinesterase inhibition by rivastigmine, a finding, which is likely to be of importance for the clinical effects.
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| 5. |
- Bjartmar, Lisa, 1966-
(författare)
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Pharmacological and Developmental Aspects on Neuronal Plasticity
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neuronal plasticity means the ability of the brain, its cells and networks to adapt and adjust to new challenges, a process which is ongoing throughout life. The goal of this thesis was to gain better understanding of the molecular events that follow different types of stimulations of brain structures such as the hippocampus, a key region for cognitive functions with overriding control on the corticosteroid system. A better knowledge of the mechanisms involved in neuronal plasticity is fundamental in the development of strategies for improving health in patients suffering from major depression or cognitive disorders such as Alzheimer’s disease.Antidepressant drugs induce the expression of several genes involved in neuronal plasticity, a mechanism which may explain the several weeks time lag between treatment initiation and clinical effect commonly observed in patients. Besides, there are indications that disturbances in the corticosteroid system are involved in the pathogenesis of major depression. Therefore, the mRNA expression of the glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) as well as of the immediate-early genes NGFI-A and NGFI-B was analyzed using in situ hybridization in the hippocampus and cortex after 21 days treatment with various antidepressant drugs having different monoaminergic profiles. The mRNA expression of the transcription factors was selectively increased depending on region and also on the monoaminergic profile of the drug given. Generally, drugs with less specificity for monoamines had an overall more anatomically wide-spread inducible effect.In a follow-up study the message expression of the synaptic protein NP2 was investigated in a similar setting where long-term (21 days) was compared with short-term (3 days) antidepressant treatment. In addition to the hippocampus, the medial habenula, a relay station within the limbic system was analyzed. Overall there was an upregulation of NP2 mRNA expression following long-term treatment irrespective of the monoaminergic profile of the drug. Simultaneously, NP2 mRNA was analyzed in rats exposed to enriched, normal or deprived environments respectively, an experimental setting known to affect neuronal plasticity. However, in contrast to the pharmacological treatment, this environmental stimulation did not lead to alterations in NP2 mRNA expression in any of the regions studied.Finally, the function of NP2 as well as the closely related proteins NP1 and NPR was investigated. The “knock-out mouse” technique was used to eliminate these neuronal pentraxins (NPs), both individually and in various combinations. Since previous data had suggested that the NPs are involved in synaptic development, axonal refinement in the visual system during development was analyzed in these animals. In the NP1/NP2 knock-out mice, synaptic formation, axonal development and refinement occurred at a significantly slower rate than in wild-type mice, indicating that the NPs may be necessary for activity-dependent synaptogenesis.In conclusion, the results of the studies constituting this thesis demonstrate that long-term treatment with antidepressant drugs, possessing different monoaminergic profiles, has selective effects on the expression of NGFI-A, NGFI-B, GR and MR in the mammalian brain. In general, the least selective drugs exhibit the most profound effect suggesting that induction of neuronal plasticity is more effective with multiple neuronal inputs. The results also show that NP2 expression is induced by antidepressant drugs, in contrast to environmental stimulation, supporting the presence of different pathways for inducing neuronal plasticity depending on type of stimuli. Finally, this thesis indicates that the neuronal pentraxins play an important part in synaptic development.
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| 6. |
- Garcia, J., et al.
(författare)
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Association of insulin-like growth factor-1 receptor polymorphism in dementia
- 2006
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Ingår i: Dementia and Geriatric Cognitive Disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 22:5-6, s. 439-444
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Tidskriftsartikel (refereegranskat)abstract
- There is an increasing interest in how oxidative stress can cause cells to go into apoptosis in both normal ageing and in neurodegenerative disorders. Previous research has implicated insulin-like growth factor-1 (IGF-1) as being involved in the pathogenesis in Alzheimer's disease (AD) by protecting the neurons through reducing neuronal susceptibility to oxidative stress. IGF-1 receptor (IGF-1R) polymorphisms alter cerebral and systemic levels of IGF-1 and may alter the function of the receptor. We genotyped the IGF-1R gene by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) to assess whether this gene polymorphism can be linked to dementia. We used leukocyte DNA from 72 patients with AD, 75 patients with vascular dementia (VaD), 14 patients with mixed dementia (AD+VaD), and a control group consisting of 209 individuals without a history of progressive neurological disorders. Analysis of gene frequency for gender revealed a significant difference between female VaD patients and female controls carrying at least one A allele (OR = 1.8, CI 95% 1.1-2.9, p = 0.02), but not for male patients. In addition, we found a strong tendency to a difference between all cases of female dementia patients and controls carrying the A allele (OR = 1.5, CI 95% 0.99-2.2, p = 0.054). Our results suggest that the A allele of IGF-1R may be involved in the pathogenesis of VaD in females. Copyright © 2006 S. Karger AG.
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| 7. |
- Mattsson, Niklas, 1979, et al.
(författare)
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CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment.
- 2009
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Ingår i: JAMA : the journal of the American Medical Association. - : American Medical Association (AMA). - 1538-3598 .- 0098-7484. ; 302:4, s. 385-93
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Small single-center studies have shown that cerebrospinal fluid (CSF) biomarkers may be useful to identify incipient Alzheimer disease (AD) in patients with mild cognitive impairment (MCI), but large-scale multicenter studies have not been conducted. OBJECTIVE: To determine the diagnostic accuracy of CSF beta-amyloid(1-42) (Abeta42), total tau protein (T-tau), and tau phosphorylated at position threonine 181 (P-tau) for predicting incipient AD in patients with MCI. DESIGN, SETTING, AND PARTICIPANTS: The study had 2 parts: a cross-sectional study involving patients with AD and controls to identify cut points, followed by a prospective cohort study involving patients with MCI, conducted 1990-2007. A total of 750 individuals with MCI, 529 with AD, and 304 controls were recruited by 12 centers in Europe and the United States. Individuals with MCI were followed up for at least 2 years or until symptoms had progressed to clinical dementia. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive and negative likelihood ratios (LRs) of CSF Abeta42, T-tau, and P-tau for identifying incipient AD. RESULTS: During follow-up, 271 participants with MCI were diagnosed with AD and 59 with other dementias. The Abeta42 assay in particular had considerable intersite variability. Patients who developed AD had lower median Abeta42 (356; range, 96-1075 ng/L) and higher P-tau (81; range, 15-183 ng/L) and T-tau (582; range, 83-2174 ng/L) levels than MCI patients who did not develop AD during follow-up (579; range, 121-1420 ng/L for Abeta42; 53; range, 15-163 ng/L for P-tau; and 294; range, 31-2483 ng/L for T-tau, P < .001). The area under the receiver operating characteristic curve was 0.78 (95% confidence interval [CI], 0.75-0.82) for Abeta42, 0.76 (95% CI, 0.72-0.80) for P-tau, and 0.79 (95% CI, 0.76-0.83) for T-tau. Cut-offs with sensitivity set to 85% were defined in the AD and control groups and tested in the MCI group, where the combination of Abeta42/P-tau ratio and T-tau identified incipient AD with a sensitivity of 83% (95% CI, 78%-88%), specificity 72% (95% CI, 68%-76%), positive LR, 3.0 (95% CI, 2.5-3.4), and negative LR, 0.24 (95% CI, 0.21-0.28). The positive predictive value was 62% and the negative predictive value was 88%. CONCLUSIONS: This multicenter study found that CSF Abeta42, T-tau, and P-tau identify incipient AD with good accuracy, but less accurately than reported from single-center studies. Intersite assay variability highlights a need for standardization of analytical techniques and clinical procedures.
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| 8. |
- Nägga, Katarina, 1962-, et al.
(författare)
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Evaluation of factors of importance for clinical dementia diagnosis
- 2005
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Ingår i: Dementia and Geriatric Cognitive Disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 19:5-6, s. 289-298
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Tidskriftsartikel (refereegranskat)abstract
- Diagnosing clinical dementia is based on an assessment of different variables, such as the patient’s medical history, known risk factors, and biochemical features. Partial least squares discriminant analysis was used to evaluate variables of importance for diagnosing dementia in a clinical dementia population. Polymorphism for genotypes of glutathione S-transferase (GST) and sulfotransferase 1A1, hypothetically of importance in dementia disorders, was also included in the analysis. The study population consisted of 73 patients with Alzheimer’s disease (AD), 14 with mixed dementia, 75 patients with vascular dementia, and 28 control cases. We found that several of the variables, such as the presence of ApoE4 allele, high cerebrospinal fluid levels of total tau protein, low levels of β-amyloid<sub>(1–42)</sub>, and a low score on the Mini-Mental State Examination, facilitated a discrimination between the diagnoses compared with the controls. The different diagnoses overlapped. There were indications that genotypes of GSTs contributed to a subgrouping within AD.
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| 9. |
- Zheng, Lin, 1978-, et al.
(författare)
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Autophagy of amyloid beta-protein in differentiated neuroblastoma cells exposed to oxidative stress
- 2006
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Ingår i: Neuroscience Letters. - : Elsevier BV. - 0304-3940 .- 1872-7972. ; 394:3, s. 184-189
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Tidskriftsartikel (refereegranskat)abstract
- Oxidative stress is considered important for the pathogenesis of Alzheimer disease (AD), which is characterized by the formation of senile plaques rich in amyloid beta-protein (Aβ). Aβ cytotoxicity has been found dependent on lysosomes, which are abundant in AD neurons and are shown to partially co-localize with Aβ. To determine whether oxidative stress has any influence on the relationship between lysosomes and Aβ1-42 (the most toxic form of Aβ), we studied the effect of hyperoxia (40% versus 8% ambient oxygen) on the intracellular localization of Aβ1-42 (assessed by immunocytochemistry) in retinoic acid differentiated SH-SY5Y neuroblastoma cells maintained in serum-free OptiMEM medium. In control cells, Aβ1-42 was mainly localized to small non-lysosomal cytoplasmic granules. Only occasionally Aβ1-42 was found in large (over 1 μm) lysosomal-associated membrane protein 2 positive vacuoles, devoid of the early endosomal marker rab5. These large Aβ1-42-containing lysosomes were not detectable in the presence of serum (known to suppress autophagy), while their number increased dramatically (up to 24-fold) after exposure of cells to hyperoxia during 5 days. Activation of autophagy by hyperoxia was confirmed by transmission electron microscopy. Furthermore, an inhibitor of autophagic sequestration 3-methyladenine prevented the accumulation of Aβ1-42-positive lysosomes due to hyperoxia. In parallel experiments, intralysosomal accumulation of Aβ1-40 following oxidative stress has been found as well. The results suggest that Aβ can be autophagocytosed and its accumulation within neuronal lysosomes is enhanced by oxidative stress. © 2005 Elsevier Ireland Ltd. All rights reserved.
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| 10. |
- Zheng, Lin, et al.
(författare)
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Oxidative stress and Alzheimer disease - The autophagy connection?
- 2006
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Ingår i: AUTOPHAGY. - 1554-8627. ; 2:2, s. 143-145
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Tidskriftsartikel (refereegranskat)abstract
- Intraneuronal accumulation of amyloid beta-protein (A beta) is believed to be responsible for degeneration and apoptosis of neurons and consequent senile plaque formation in Alzheimer disease (AD), the main cause of senile dementia. Oxidative stress, an early determinant of AD, has been recently found to induce intralysosomal A beta accumulation in cultured differentiated neuroblastoma cells through activation of macroautophogy. Because A beta is known to destabilize lysosomal membranes, potentially resulting in apoptotic cell death, this finding suggests the involvement of oxidative stress-induced macroautophagy in the pathogenesis of AD.
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