| 21. |
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| 22. |
- Benner, Mats, et al.
(författare)
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Modet att ta ansvar
- 2008
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Ingår i: Forska lagom och vara världsbäst? Sverige inför forskningens globala strukturomvandling.. ; , s. 155-166
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 23. |
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| 24. |
- Björklund, Anders, et al.
(författare)
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Repairing the Parkinson Brain
- 2021
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Ingår i: Journal of Parkinson's Disease. - 1877-718X. ; 11:s2, s. 123-125
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Tidskriftsartikel (refereegranskat)
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| 25. |
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| 26. |
- Björkqvist, Maria, et al.
(författare)
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A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease.
- 2008
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 205, s. 1869-1877
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Tidskriftsartikel (refereegranskat)abstract
- Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities. We examined the peripheral immune system and found widespread evidence of innate immune activation detectable in plasma throughout the course of HD. Interleukin 6 levels were increased in HD gene carriers with a mean of 16 years before the predicted onset of clinical symptoms. To our knowledge, this is the earliest plasma abnormality identified in HD. Monocytes from HD subjects expressed mutant huntingtin and were pathologically hyperactive in response to stimulation, suggesting that the mutant protein triggers a cell-autonomous immune activation. A similar pattern was seen in macrophages and microglia from HD mouse models, and the cerebrospinal fluid and striatum of HD patients exhibited abnormal immune activation, suggesting that immune dysfunction plays a role in brain pathology. Collectively, our data suggest parallel central nervous system and peripheral pathogenic pathways of immune activation in HD.
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| 27. |
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| 28. |
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| 29. |
- Björkqvist, Maria, et al.
(författare)
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Progressive alterations in the hypothalamic-pituitary-adrenal axis in the R6/2 transgenic mouse model of Huntington's disease
- 2006
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 15:10, s. 1713-1721
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Tidskriftsartikel (refereegranskat)abstract
- Huntington's disease (HD) is characterized by a triad of motor, psychiatric and cognitive symptoms. Although many of these symptoms are likely to be related to central nervous system pathology, others may be due to changes in peripheral tissues. The R6/2 mouse, a transgenic model of HD expressing exon 1 of the human HD gene, develops progressive alterations in the hypothalamic-pituitary-adrenal axis, reminiscent of a Cushing-like syndrome. We observed muscular atrophy, reduced bone mineral density, abdominal fat accumulation and insulin resistance in the mice. All these changes could be consequences of increased glucocorticoid levels. Indeed, hypertrophy of the adrenal cortex and a progressive increase in serum and urine corticosterone levels were found in R6/2 mice. In addition, the intermediate pituitary lobe was markedly enlarged and circulating adreno-corticotrophic hormone (ACTH) increased. Under normal conditions dopamine represses the ACTH expression. In the R6/2 mice, however, the expression of pituitary dopamine D2 receptors was reduced by half, possibly explaining the increase in ACTH. Urinary samples from 82 HD patients and 68 control subjects were analysed for cortisol: in accord with the observations in the R6/2 mice, urinary cortisol increased in parallel with disease progression. This progressive increase in cortisol may contribute to the clinical symptoms, such as muscular wasting, mood changes and some of the cognitive deficits that occur in HD.
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| 30. |
- Björkqvist, Maria, et al.
(författare)
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The R6/2 transgenic mouse model of Huntington's disease develops diabetes due to deficient {beta}-cell mass and exocytosis.
- 2005
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 14:5, s. 565-574
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Tidskriftsartikel (refereegranskat)abstract
- Diabetes frequently develops in Huntington's disease (HD) patients and in transgenic mouse models of HD such as the R6/2 mouse. The underlying mechanisms have not been clarified. Elucidating the pathogenesis of diabetes in HD would improve our understanding of the molecular mechanisms involved in HD neuropathology. With this aim, we examined our colony of R6/2 mice with respect to glucose homeostasis and islet function. At week 12, corresponding to end-stage HD, R6/2 mice were hyperglycemic and hypoinsulinemic and failed to release insulin in an intravenous glucose tolerance test. In vitro, basal and glucose-stimulated insulin secretion was markedly reduced. Islet nuclear huntingtin inclusions increased dramatically over time, predominantly in ß-cells. ß-cell mass failed to increase normally with age in R6/2 mice. Hence, at week 12, ß-cell mass and pancreatic insulin content in R6/2 mice were 35±5 and 16±3% of that in wild-type mice, respectively. The normally occurring replicating cells were largely absent in R6/2 islets, while no abnormal cell death could be detected. Single cell patch-clamp experiments revealed unaltered electrical activity in R6/2 ß-cells. However, exocytosis was virtually abolished in ß- but not in {alpha}-cells. The blunting of exocytosis could be attributed to a 96% reduction in the number of insulin-containing secretory vesicles. Thus, diabetes in R6/2 mice is caused by a combination of deficient ß-cell mass and disrupted exocytosis.
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