| 1. |
- Mathiesen Janiurek, Mette, et al.
(författare)
-
Apolipoprotein M-bound sphingosine-1-phosphate regulates blood-brain barrier paracellular permeability and transcytosis
- 2019
-
Ingår i: eLife. - 2050-084X. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- The blood-brain barrier (BBB) is formed by the endothelial cells lining cerebral microvessels, but how blood-borne signaling molecules influence permeability is incompletely understood. We here examined how the apolipoprotein M (apoM)-bound sphingosine 1-phosphate (S1P) signaling pathway affects the BBB in different categories of cerebral microvessels using ApoM deficient mice (Apom-/-). We used two-photon microscopy to monitor BBB permeability of sodium fluorescein (376 Da), Alexa Fluor (643 Da), and fluorescent albumin (45 kDA). We show that BBB permeability to small molecules increases in Apom-/- mice. Vesicle-mediated transfer of albumin in arterioles increased 3 to 10-fold in Apom-/- mice, whereas transcytosis in capillaries and venules remained unchanged. The S1P receptor 1 agonist SEW2871 rapidly normalized paracellular BBB permeability in Apom-/- mice, and inhibited transcytosis in penetrating arterioles, but not in pial arterioles. Thus, apoM-bound S1P maintains low paracellular BBB permeability in all cerebral microvessels and low levels of vesicle-mediated transport in penetrating arterioles.
|
|
| 2. |
|
|
| 3. |
- Sjögren, Marie, et al.
(författare)
-
Leptin deficiency reverses high metabolic state and weight loss without affecting central pathology in the R6/2 mouse model of Huntington's disease
- 2019
-
Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961 .- 1095-953X. ; 132
-
Tidskriftsartikel (refereegranskat)abstract
- © 2019 Body weight has been shown to be a predictor of clinical progression in Huntington's disease (HD). Alongside widespread neuronal pathology, both HD patients and the R6/2 mouse model of HD exhibit weight loss and increased energy expenditure, providing a rationale for targeting whole-body energy metabolism in HD. Leptin-deficient mice display low energy expenditure and increased body weight. We therefore hypothesized that normalizing energy metabolism in R6/2 mice, utilizing leptin- deficiency, would lead to a slower disease progression in the R6/2 mouse. In this study, we show that R6/2 mice on a leptin-deficient genetic background display increased body weight and increased fat mass compared to R6/2 mice, as well as wild type littermates. The increased body weight was accompanied by low energy expenditure, illustrated by a reduction in respiratory exchange rate. Leptin-deficient R6/2 mice had large white adipocytes with white adipocyte gene expression characteristics, in contrast to white adipose tissue in R6/2 mice, where white adipose tissue showed signs of browning. Leptin-deficient R6/2 mice did not exhibit improved neuropathological measures. Our results indicate that lowering energy metabolism in HD, by increasing fat mass and reducing respiratory exchange rate, is not sufficient to affect neuropathology. Further studies targeting energy metabolism in HD are warranted.
|
|
| 4. |
- Soylu Kucharz, Rana
(författare)
-
Hypothalamic and Metabolic Dysfunction in Genetic Models of Huntington’s Disease
- 2016
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Huntington’s disease (HD) is caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene. HD is an inherited progressive neurodegenerative disorder manifested by the wide array of motor dysfunctions, as well as non-motor symptoms. The latter include metabolic dysfunction and psychiatric deficits, such as depression and anxiety, are often observed in patients andanimal models of HD and may precede motor symptoms by many years. Although recent evidence suggests that early non-motor symptoms may be caused by detrimental changes in the hypothalamus, a key brain region involved in modulating metabolism and emotions, the direct contribution of hypothalamic dysfunction to the development of the HD phenotype was never addressedin detail. This prompted us to explore the effects of mutant HTT expression in the hypothalamus and the cellular and molecular mechanisms involved in the development of non-motor symptoms. We show that the conditional BACHD mouse model of HD exhibit the obese phenotype with impaired glucose metabolism and leptin resistance, and the phenotype can be rescued by the inactivation of mutant HTT selectively in the hypothalamus with viral vector-mediated delivery of Cre recombinase. In reverse-design experiments, we demonstrate that viral vector-mediated expression of mutant HTT fragment locally in the hypothalamus is sufficient to recapitulate the metabolic dysfunction (Paper I).Furthermore, we suggest that the effects of HD hypothalamic dysfunction may be sex-specific and we imply the importance of specific cell populations to the development and progression of the disease. The paraventricular nucleus (PVN) is an important region of the hypothalamus in which patients and HD animal models exhibit cell loss and reduction in neuropeptide expression.As single-minded 1 (Sim1) transcription factor is a widely expressed in the PVN, we conditionally inactivated mutant HTT expression in Sim1 expressing cells of BACHD mice using a cross-breeding strategy. We show that the metabolic and depressive like phenotype have trends towards a rescue effect in male BACHD mice. In addition, we demonstrate that the hypothalamicpituitary-gonadal axis is altered in male BACHD mice with a reduced number of gonadotropin-releasing hormone expressing cells in the anterior hypothalamic area along with increased testes weight (Paper II).Lastly, we reveal the long-term effects of hypothalamic overexpression of mutant or wild-type form of HTT. We found that viral vector-mediated expression of both form of the HTT leads to metabolic dysfunction at 1 year post-injection, with the speed of progression of metabolic dysfunction correlating with the length of polyQ repeats. In addition, our data demonstrates that theselective expression of mutant HTT in the hypothalamus has detrimental effects on brown adipose tissue function and in turn energy balance by disrupting the hypothalamic dopaminergic pathway involved in thermogenesis (Paper III).Taken together, we provide the evidence for a causal link between mutant HTT expression in the hypothalamus and the metabolic dysfunction in HD. These findings represent a significant contribution to understanding HD pathology, rendering the hypothalamus as an attractive target for developing new treatment strategies for the disease.
|
|
| 5. |
- Soylu-Kucharz, Rana, et al.
(författare)
-
Metabolic and behavioral effects of mutant huntingtin deletion in Sim1 neurons in the BACHD mouse model of Huntington's disease
- 2016
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
-
Tidskriftsartikel (refereegranskat)abstract
- Hypothalamic pathology, metabolic dysfunction and psychiatric symptoms are part of Huntington disease (HD), which is caused by an expanded CAG repeat in the huntingtin (HTT) gene. Inactivation of mutant HTT selectively in the hypothalamus prevents the development of metabolic dysfunction and depressive-like behavior in the BACHD mouse model. The hypothalamic paraventricular nucleus (PVN) is implicated in metabolic and emotional control, therefore we here tested whether inactivation of mutant HTT in the PVN affects metabolic and psychiatric manifestations of HD in BACHD mice. BACHD mice were crossed with mice expressing Cre-recombinase under the Sim1 promoter (Sim1-Cre) to inactivate mutant HTT in Sim1 expressing cells, i.e. the PVN of the hypothalamus. We found that inactivation of mutant HTT in Sim1 cells had a sex-specific effect on both the metabolic and the psychiatric phenotype, as these phenotypes were no longer different in male BACHD/Sim1-Cre mice compared to wild-type littermates. We also found a reduced number of GnRH neurons specifically in the anterior hypothalamus and an increased testes weight in male BACHD mice compared to wild-type littermates. Taken together, expression of mutant HTT in Sim1 cells may play a role for the development of metabolic dysfunction and depressive-like behavior in male BACHD mice.
|
|
| 6. |
- Soylu-Kucharz, Rana, et al.
(författare)
-
Neurofilament light protein in CSF and blood is associated with neurodegeneration and disease severity in Huntington's disease R6/2 mice
- 2017
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- There is an unmet need to reliably and non-invasively monitor disease progression in preclinical Huntington's disease (HD) models. As a marker of axonal damage, neurofilament light chain (NfL) has been suggested a marker for neurodegeneration. NfL concentrations in blood and CSF were recently shown to have prognostic value for clinical HD progression and brain atrophy. We therefore hypothesized that CSF and blood NfL concentrations could be useful preclinical HD markers, reflecting underlying pathology. To test our hypothesis we utilized the R6/2 mouse model of HD and measured NfL concentrations in CSF and serum using the ultrasensitive Single molecule array (Simoa) platform. In addition, we assessed HD mouse disease characteristics. We found robust increases of NfL in CSF and serum in R6/2 mice compared to wild-type littermates. CSF and serum concentrations of NfL were significantly correlated, suggesting similar marker potential of serum NfL. CSF and serum concentrations of NfL correlated with disease severity, as assessed by striatal volume and body weight loss. We here provide evidence that CSF and blood NfL concentrations can be used as accessible and reliable pre-clinical HD markers. This will be of potential use for monitoring HD mouse model disease progression and evaluating preclinical disease-modifying treatment response.
|
|
| 7. |
- Soylu, Rana, et al.
(författare)
-
Hypothalamic overexpression of mutant huntingtin causes dysregulation of brown adipose tissue.
- 2015
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
-
Tidskriftsartikel (refereegranskat)abstract
- Expression of mutant huntingtin (htt) protein has been shown to cause metabolic imbalance in animal models of Huntington disease (HD). The pathways involved are not fully understood but dysfunction of both the hypothalamus and brown adipose tissue (BAT) has been implicated. Here we show that targeted expression of mutant HTT in the hypothalamus leads to loss of the A13 dopaminergic cell group located in the zona incerta and reduced mRNA expression of neuropeptide Y1 receptor in the hypothalamus. Furthermore, this is accompanied by downregulation of uncoupling protein 1 expression and PPARγ coactivator-1 alpha in BAT and a rapid body weight gain. Taken together, our data might provide a mechanistic link between expression of mutant HTT, reduced activity of a hypothalamic dopaminergic pathway and dysfunction of BAT and in part explain the development of an obese phenotype in HD mouse models.
|
|
| 8. |
- Wiesner, Diana, et al.
(författare)
-
Low dietary protein content alleviates motor symptoms in mice with mutant dynactin/dynein-mediated neurodegeneration.
- 2015
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 24:8, s. 2228-2240
-
Tidskriftsartikel (refereegranskat)abstract
- Mutations in components of the molecular motor dynein/dynactin lead to neurodegenerative diseases of the motor system or atypical parkinsonism. These mutations are associated with prominent accumulation of vesicles involved in autophagy and lysosomal pathways, and with protein inclusions. Whether alleviating these defects would affect motor symptoms remain unknown. Here, we show that a mouse model expressing low levels of disease linked-G59S mutant dynactin p150(Glued) develops motor dysfunction >8 months before loss of motor neurons or dopaminergic degeneration is observed. Abnormal accumulation of autophagosomes and protein inclusions were efficiently corrected by lowering dietary protein content, and this was associated with transcriptional upregulations of key players in autophagy. Most importantly this dietary modification partially rescued overall neurological symptoms in these mice after onset. Similar observations were made in another mouse strain carrying a point mutation in the dynein heavy chain gene. Collectively, our data suggest that stimulating the autophagy/lysosomal system through appropriate nutritional intervention has significant beneficial effects on motor symptoms of dynein/dynactin diseases even after symptom onset.
|
|
