| 1. |
- Clemensson, Erik Karl Håkan, et al.
(författare)
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The BACHD rat model of Huntington disease shows slowed learning in a Go/No-Go-like test of visual discrimination
- 2019
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Ingår i: Behavioural Brain Research. - : Elsevier. - 0166-4328 .- 1872-7549. ; 359, s. 116-126
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Tidskriftsartikel (refereegranskat)abstract
- Huntington disease is a hereditary neurodegenerative disease, in which patients display a broad range of clinical symptoms. Among these, impaired inhibitory control has been noted. The BACHD rat is a recently developed and established transgenic animal model for Huntington disease, and characterizing the presence of Huntington disease-like behavioural phenotypes in these animals is of importance. Prior studies have indicated that BACHD rats suffer from impaired inhibitory control, although further studies are necessary to fully understand the scope and specific nature of these phenotypes. In the current study, BACHD rats were trained to perform a Go/No-Go-like test of visual discrimination, akin to behavioural tests that have revealed suspected response inhibition impairments in Huntington disease patients. The results indicate that although BACHD rats showed a slow rate of learning to inhibit responses on No-Go trials, once they had learned to handle the basic discrimination, they had an unchanged ability to withhold lever responses during extended periods of time. This suggests that BACHD rats have specific impairments when applying inhibitory control to a new or changed situation. The findings are in line with previous studies of BACHD rats and support the continued use and characterization of this animal model.
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| 2. |
- Al-Sabri, Mohamed H., et al.
(författare)
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The regulatory role of AP-2 beta in monoaminergic neurotransmitter systems : insights on its signalling pathway, linked disorders and theragnostic potential
- 2022
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Ingår i: Cell & Bioscience. - : BioMed Central (BMC). - 2045-3701. ; 12:1
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Forskningsöversikt (refereegranskat)abstract
- Monoaminergic neurotransmitter systems play a central role in neuronal function and behaviour. Dysregulation of these systems gives rise to neuropsychiatric and neurodegenerative disorders with high prevalence and societal burden, collectively termed monoamine neurotransmitter disorders (MNDs). Despite extensive research, the transcriptional regulation of monoaminergic neurotransmitter systems is not fully explored. Interestingly, certain drugs that act on these systems have been shown to modulate central levels of the transcription factor AP-2 beta (AP-2 beta, gene: TFAP2B). AP-2 beta regulates multiple key genes within these systems and thereby its levels correlate with monoamine neurotransmitters measures; yet, its signalling pathways are not well understood. Moreover, although dysregulation of TFAP2B has been associated with MNDs, the underlying mechanisms for these associations remain elusive. In this context, this review addresses AP-2 beta, considering its basic structural aspects, regulation and signalling pathways in the controlling of monoaminergic neurotransmitter systems, and possible mechanisms underpinning associated MNDS. It also underscores the significance of AP-2 beta as a potential diagnostic biomarker and its potential and limitations as a therapeutic target for specific MNDs as well as possible pharmaceutical interventions for targeting it. In essence, this review emphasizes the role of AP-2 beta as a key regulator of the monoaminergic neurotransmitter systems and its importance for understanding the pathogenesis and improving the management of MNDs.
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| 3. |
- Alsehli, Ahmed M., et al.
(författare)
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Differential associations of statin treatment and polymorphism in genes coding for HMGCR and PCSK9 to risk for insomnia
- 2021
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Ingår i: Frontiers in Bioscience-Landmark. - : Frontiers Media S.A.. - 2768-6701 .- 2768-6698. ; 26:12, s. 1453-1463
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Statins have been linked to an increased risk for insomnia, but the literature is controversial. Moreover, it is unknown, if the potential effects are directly related to the inhibition of the statin target HMGCR, the subsequently lowered cholesterol levels, or other off-target effects of statins. Aims: To investigate the association of statin treatment and genetic proxies of cholesterol lowering drugs with the risk for insomnia and chronotype in a large population-based cohort. Methods: A cross-sectional cohort study based on baseline data collected between 2006–2010 in UK biobank cohort was conducted. European participants without any history of psychiatric/neurological disorders or of stroke and with available genetic data as well as information on statin use were included in the present study. Self-reported measures of insomnia and chronotype were analysed (a) in statin users versus control subjects, (b) subjects carrying single nucleotide polymorphisms (SNPs) in the HMGCR gene, which are associated with reduced enzymatic function and lower cholesterol levels (rs17238484 and rs12916) and (c) subjects carrying a SNP in the PCSK9 gene (rs1159147), which leads to lower cholesterol levels independent of HMGCR. The main analysis were performed using multivariable regression models. Statin treatment and SNPs in HMGCR and PCSK9 genes were used as exposures and main outcomes were insomnia and chronotype. Results: A total of 206,801participants (mean [SD] age, 57.5 [7.9] years; 56% women; 20% statin users) were included in the present study. Statin users had an increased risk of insomnia compared to controls (odds ratio [95% CI], 1.07 [1.03 to 1.11]; p = 1.42 × 10−4). A similar effect was observed for PCSK9 rs11591147-T allele (1.07 [1.01–1.14]; 0.014), while the two gene variants of HMGCR were associated with a reduced risk for insomnia (rs17238484-G: 0.97 [0.95 to 0.99]; 0.014 and rs12916-T: 0.97 [0.96 to 0.99]; 0.002). In regard to chronotype, there was no effect of either statin treatment or HMGCR SNPs, but the PCSK9 rs11591147-T allele was associated with a higher evening preference (1.17 [1.06 to 1.29]; 0.001). Conclusion: Our data suggests that statin treatment can pose an increased risk for insomnia in in the European population. Interestingly, there was no agreement between the effects of statins and the effects of reduced HMGCR activity based on genetic variants, suggesting that the observed unfavourable effect of statins on sleep is conveyed through other targets. This further explains why the literature on statin effects on sleep is not conclusive. Finally our data encourage further investigations into the molecular processes linking statins, HMGCR and PCSK9 to sleep behaviour.
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| 4. |
- Alsehli, Ahmed M., et al.
(författare)
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The Cognitive Effects of Statins are Modified by Age
- 2020
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- To reveal new insights into statin cognitive effects, we performed an observational study on a population-based sample of 245,731 control and 55,114 statin-taking individuals from the UK Biobank. Cognitive performance in terms of reaction time, working memory and fluid intelligence was analysed at baseline and two follow-ups (within 5-10 years). Subjects were classified depending on age (up to 65 and over 65 years) and treatment duration (1-4 years, 5-10 years and over 10 years). Data were adjusted for health- and cognition-related covariates. Subjects generally improved in test performance with repeated assessment and middle-aged persons performed better than older persons. The effect of statin use differed considerably between the two age groups, with a beneficial effect on reaction time in older persons and fluid intelligence in both age groups, and a negative effect on working memory in younger subjects. Our analysis suggests a modulatory impact of age on the cognitive side effects of statins, revealing a possible reason for profoundly inconsistent findings on statin-related cognitive effects in the literature. The study highlights the importance of characterising modifiers of statin effects to improve knowledge and shape guidelines for clinicians when prescribing statins and evaluating their side effects in patients.
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| 5. |
- Alsehli, Ahmed M., et al.
(författare)
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The Statin Target HMG-Coenzyme a Reductase (Hmgcr) Regulates Sleep Homeostasis in Drosophila
- 2022
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Ingår i: Pharmaceuticals. - : MDPI AG. - 1424-8247. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Statins, HMG Coenzyme A Reductase (HMGCR) inhibitors, are a first-line therapy, used to reduce hypercholesterolemia and the risk for cardiovascular events. While sleep disturbances are recognized as a side-effect of statin treatment, the impact of statins on sleep is under debate. Using Drosophila, we discovered a novel role for Hmgcr in sleep modulation. Loss of pan-neuronal Hmgcr expression affects fly sleep behavior, causing a decrease in sleep latency and an increase in sleep episode duration. We localized the pars intercerebralis (PI), equivalent to the mammalian hypothalamus, as the region within the fly brain requiring Hmgcr activity for proper sleep maintenance. Lack of Hmgcr expression in the PI insulin-producing cells recapitulates the sleep effects of pan-neuronal Hmgcr knockdown. Conversely, loss of Hmgcr in a different PI subpopulation, the corticotropin releasing factor (CRF) homologue-expressing neurons (DH44 neurons), increases sleep latency and decreases sleep duration. The requirement for Hmgcr activity in different neurons signifies its importance in sleep regulation. Interestingly, loss of Hmgcr in the PI does not affect circadian rhythm, suggesting that Hmgcr regulates sleep by pathways distinct from the circadian clock. Taken together, these findings suggest that Hmgcr activity in the PI is essential for proper sleep homeostasis in flies.
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| 6. |
- Jamshidnejad-Tosaramandani, Tahereh, et al.
(författare)
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Statins and cognition : Modifying factors and possible underlying mechanisms
- 2022
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Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media S.A.. - 1663-4365 .- 1663-4365. ; 14
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Forskningsöversikt (refereegranskat)abstract
- Statins are a class of widely prescribed drugs used to reduce low-density lipoprotein cholesterol (LDL-C) and important to prevent cardiovascular diseases (CVD). Most statin users are older adults with CVD, who are also at high risk of cognitive decline. It has been suggested that statins can alter cognitive performance, although their positive or negative effects are still debated. With more than 200 million people on statin therapy worldwide, it is crucial to understand the reasons behind discrepancies in the results of these studies. Here, we review the effects of statins on cognitive function and their association with different etiologies of dementia, and particularly, Alzheimer's disease (AD). First, we summarized the main individual and statin-related factors that could modify the cognitive effects of statins. Second, we proposed the underlying mechanisms for the protective and adverse effects of statins on cognitive performance. Finally, we discussed potential causes of discrepancies between studies and suggested approaches to improve future studies assessing the impact of statins on dementia risk and cognitive function.
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| 7. |
- Weber, Jonasz Jeremiasz, et al.
(författare)
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Olesoxime in neurodegenerative diseases : Scrutinising a promising drug candidate
- 2019
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Ingår i: Biochemical Pharmacology. - : Elsevier BV. - 0006-2952 .- 1356-1839. ; 168, s. 305-318
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Forskningsöversikt (refereegranskat)abstract
- Over the last years, the experimental compound olesoxime, a mitochondria-targeting cholesterol derivative, has emerged as a promising drug candidate for neurodegenerative diseases. Numerous preclinical studies have successfully proved olesoxime's neuroprotective properties in cell and animal models of clinical conditions such as amyotrophic lateral sclerosis, Huntington disease, Parkinson disease, peripheral neuropathy and spinal muscular atrophy. The beneficial effects were attributed to olesoxime's potential impact on oxidative stress, mitochondrial permeability transition or cholesterol homoeostasis. Although no significant benefits have been demonstrated in patients of amyotrophic lateral sclerosis, and only the first 12 months of a phase II/III clinical trial showed an improvement in motor symptoms of spinal muscular atrophy, this orphan drug may still offer undiscovered potential in the treatment of neurological diseases. In our earlier preclinical studies, we demonstrated that administration of olesoxime in mouse and rat models of Huntington disease improved psychiatric and molecular phenotypes. Aside from stabilising mitochondrial function, the drug reduced the overactivation of calpains, a class of calcium-dependent proteases entangled in neurodegenerative conditions. This observation may be credited to olesoxime's action on calcium dyshomeostasis, a further hallmark in neurodegeneration, and linked to its targets TSPO and VDAC, two proteins of the outer mitochondrial membrane associated with mitochondrial calcium handling. Further research into the mode of action of olesoxime under pathological conditions, including its effect on neuronal calcium homeostasis, may strengthen the untapped potential of olesoxime or other similar compounds as a therapeutic for neurodegenerative diseases.
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| 8. |
- Williams, Michael J., et al.
(författare)
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The Statin Target Hmgcr Regulates Energy Metabolism and Food Intake through Central Mechanisms
- 2022
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Ingår i: Cells. - : MDPI. - 2073-4409. ; 11:6
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Tidskriftsartikel (refereegranskat)abstract
- The statin drug target, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), is strongly linked to body mass index (BMI), yet how HMGCR influences BMI is not understood. In mammals, studies of peripheral HMGCR have not clearly identified a role in BMI maintenance and, despite considerable central nervous system expression, a function for central HMGCR has not been determined. Similar to mammals, Hmgcr is highly expressed in the Drosophila melanogaster brain. Therefore, genetic and pharmacological studies were performed to identify how central Hmgcr regulates Drosophila energy metabolism and feeding behavior. We found that inhibiting Hmgcr, in insulin-producing cells of the Drosophila pars intercerebralis (PI), the fly hypothalamic equivalent, significantly reduces the expression of insulin-like peptides, severely decreasing insulin signaling. In fact, reducing Hmgcr expression throughout development causes decreased body size, increased lipid storage, hyperglycemia, and hyperphagia. Furthermore, the Hmgcr induced hyperphagia phenotype requires a conserved insulin-regulated alpha-glucosidase, target of brain insulin (tobi). In rats and mice, acute inhibition of hypothalamic Hmgcr activity stimulates food intake. This study presents evidence of how central Hmgcr regulation of metabolism and food intake could influence BMI.
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