| 11. |
- Hult Lundh, Sofia, et al.
(författare)
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Expression of Mutant Huntingtin in Leptin Receptor-Expressing Neurons Does Not Control the Metabolic and Psychiatric Phenotype of the BACHD Mouse.
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:12
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Tidskriftsartikel (refereegranskat)abstract
- Metabolic and psychiatric disturbances occur early on in the clinical manifestation of Huntington's disease (HD), a neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene. Hypothalamus has emerged as an important site of pathology and alterations in this area and its neuroendocrine circuits may play a role in causing early non-motor symptoms and signs in HD. Leptin is a hormone that controls energy homeostasis by signaling through leptin receptors in the hypothalamus. Disturbed leptin action is implicated in both obesity and depression and altered circulating levels of leptin have been reported in both clinical HD and rodent models of the disease. Pathological leptin signaling may therefore be involved in causing the metabolic and psychiatric disturbances of HD. Here we tested the hypothesis that expression of mutant HTT in leptin receptor carrying neurons plays a role in the development of the non-motor phenotype in the BACHD mouse model. Our results show that inactivation of mutant HTT in leptin receptor-expressing neurons in the BACHD mouse using cross-breeding based on a cre-loxP system did not have an effect on the metabolic phenotype or anxiety-like behavior. The data suggest that mutant HTT disrupts critical hypothalamic pathways by other mechanisms than interfering with intracellular leptin signaling.
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| 12. |
- Hult Lundh, Sofia, et al.
(författare)
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Hypothalamic and Neuroendocrine Changes in Huntington's Disease.
- 2010
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Ingår i: Current drug targets. - 1873-5592. ; 11, s. 1237-1249
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Tidskriftsartikel (refereegranskat)abstract
- Huntington's disease (HD) is a fatal hereditary neurodegenerative disorder without satisfactory treatments nor a cure. It is caused by a CAG repeat expansion in the huntingtin gene. The clinical symptoms involve motor-, cognitive- and psychiatric disturbances. Recent studies have shown that non-motor symptoms and signs, such as mood changes, sleep disturbances and metabolic alterations often occur before the onset of overt motor impairments. The hypothalamus is one of the main regulators of emotion, sleep and metabolism, and it is therefore possible that dysfunction of the hypothalamus and neuroendocrine circuits may, at least partly, be responsible for these non-motor symptoms in HD. Several hypothalamic and neuroendocrine changes have now been identified in clinical HD as well as in rodent models of the disease. These changes could be important both in the pathogenesis of HD, constitute biomarkers to track disease progression as well as to provide novel therapeutic targets for this devastating disease. The current state of knowledge in the area of hypothalamic and neuroendocrine changes in both patients and rodent models of HD is summarized in this review, and their potential as targets for novel treatment paradigms are discussed.
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| 13. |
- Hult Lundh, Sofia, et al.
(författare)
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Hypothalamic expression of mutant huntingtin contributes to the development of depressive-like behavior in the BAC transgenic mouse model of Huntingtons disease
- 2013
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 22:17, s. 3485-3497
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Tidskriftsartikel (refereegranskat)abstract
- Psychiatric symptoms such as depression and anxiety are important clinical features of Huntingtons disease (HD). However, the underlying neurobiological substrate for the psychiatric features is not fully understood. In order to explore the biological origin of depression and anxiety in HD, we used a mouse model that expresses the human full-length mutant huntingtin, the BACHD mouse. We found that the BACHD mice displayed depressive- and anxiety-like features as early as at 2 months of age as assessed using the Porsolt forced swim test (FST), the sucrose preference test and the elevated plus maze (EPM). BACHD mice subjected to chronic treatment with the anti-depressant sertraline were not different to vehicle-treated BACHD mice in the FST and EPM. The behavioral manifestations occurred in the absence of reduced hippocampal cell proliferation/neurogenesis or upregulation of the hypothalamicpituitaryadrenal axis. However, alterations in anxiety- and depression-regulating genes were present in the hypothalamus of BACHD mice including reduced mRNA expression of neuropeptide Y, tachykinin receptor 3 and vesicular monoamine transporter type 2 as well as increased expression of cocaine and amphetamine regulated transcript. Interestingly, the orexin neuronal population in the hypothalamus was increased and showed cellular atrophy in old BACHD mice. Furthermore, inactivation of mutant huntingtin in a subset of the hypothalamic neurons prevented the development of the depressive features. Taken together, our data demonstrate that the BACHD mouse recapitulates clinical HD with early psychiatric aspects and point to the role of hypothalamic dysfunction in the development of depression and anxiety in the disease.
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| 14. |
- Hult Lundh, Sofia, et al.
(författare)
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Mutant huntingtin causes metabolic imbalance by disruption of hypothalamic neurocircuits.
- 2011
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131. ; 13:4, s. 428-439
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Tidskriftsartikel (refereegranskat)abstract
- In Huntington's disease (HD), the mutant huntingtin protein is ubiquitously expressed. The disease was considered to be limited to the basal ganglia, but recent studies have suggested a more widespread pathology involving hypothalamic dysfunction. Here we tested the hypothesis that expression of mutant huntingtin in the hypothalamus causes metabolic abnormalities. First, we showed that bacterial artificial chromosome-mediated transgenic HD (BACHD) mice developed impaired glucose metabolism and pronounced insulin and leptin resistance. Selective hypothalamic expression of a short fragment of mutant huntingtin using adeno-associated viral vectors was sufficient to recapitulate these metabolic disturbances. Finally, selective hypothalamic inactivation of the mutant gene prevented the development of the metabolic phenotype in BACHD mice. Our findings establish a causal link between mutant huntingtin expression in the hypothalamus and metabolic dysfunction, and indicate that metabolic parameters are powerful readouts to assess therapies aimed at correcting dysfunction in HD by silencing huntingtin expression in the brain.
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| 15. |
- Mathiesen Janiurek, Mette, et al.
(författare)
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Apolipoprotein M-bound sphingosine-1-phosphate regulates blood-brain barrier paracellular permeability and transcytosis
- 2019
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Ingår i: eLife. - 2050-084X. ; 8
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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.
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| 16. |
- Mikrouli, Elli, et al.
(författare)
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Increased numbers of orexin/hypocretin neurons in a genetic rat depression model.
- 2011
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Ingår i: Neuropeptides. - : Elsevier BV. - 1532-2785 .- 0143-4179. ; 45, s. 401-406
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Tidskriftsartikel (refereegranskat)abstract
- The Flinders Sensitive Line (FSL) rat is a genetic animal model of depression that displays characteristics similar to those of depressed patients including lower body weight, decreased appetite and reduced REM sleep latency. Hypothalamic neuropeptides such as orexin/hypocretin, melanin-concentrating hormone (MCH) and cocaine and amphetamine regulated transcript (CART), that are involved in the regulation of both energy metabolism and sleep, have recently been implicated also in depression. We therefore hypothesized that alterations in these neuropeptide systems may play a role in the development of the FSL phenotype with both depressive like behavior, metabolic abnormalities and sleep disturbances. In this study, we first confirmed that the FSL rats displayed increased immobility in the Porsolt forced swim test compared to their control strain, the Flinders Resistant Line (FRL), which is indicative of depressive-like behavior. We then examined the number of orexin-, MCH- and CART-immunopositive neurons in the hypothalamus using stereological analyses. We found that the total number of orexin-positive neurons was higher in the hypothalamus of female FSL rats compared to female FRL rats, whereas no changes in the MCH or CART populations could be detected between the strains. Chronic treatment with the selective serotonin reuptake inhibitor (SSRI) escitalopram reduced immobility only in the FRL rats where it also increased the number of MCH positive neurons compared to untreated rats. These findings support the view that orexin may be involved in depression and strengthen the notion that the "depressed" brain responds differently to pharmacological interventions than the normal brain.
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| 17. |
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| 18. |
- Sjögren, Marie, et al.
(författare)
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Leptin deficiency reverses high metabolic state and weight loss without affecting central pathology in the R6/2 mouse model of Huntington's disease
- 2019
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961 .- 1095-953X. ; 132
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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.
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| 19. |
- Soylu Kucharz, Rana
(författare)
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Hypothalamic and Metabolic Dysfunction in Genetic Models of Huntington’s Disease
- 2016
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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.
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| 20. |
- Soylu-Kucharz, Rana, et al.
(författare)
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IKKβ signaling mediates metabolic changes in the hypothalamus of a Huntington disease mouse model
- 2022
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Ingår i: iScience. - : Elsevier BV. - 2589-0042. ; 25:2, s. 1-16
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Tidskriftsartikel (refereegranskat)abstract
- Huntington disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. Metabolic changes are associated with HD progression, but underlying mechanisms are not fully known. As the IKKβ/NF-κB pathway is an essential regulator of metabolism, we investigated the involvement of IKKβ, the upstream activator of NF-κB in hypothalamus-specific HD metabolic changes. We expressed amyloidogenic N-terminal fragments of mutant HTT (mHTT) in the hypothalamus of mice with brain-specific ablation of IKKβ (Nestin/IKKβlox/lox) and control mice (IKKβlox/lox). We assessed effects on body weight, metabolic hormones, and hypothalamic neuropathology. Hypothalamic expression of mHTT led to an obese phenotype only in female mice. CNS-specific inactivation of IKKβ prohibited weight gain in females, which was independent of neuroprotection and microglial activation. Our study suggests that mHTT in the hypothalamus causes metabolic imbalance in a sex-specific fashion, and central inhibition of the IKKβ pathway attenuates the obese phenotype.
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