| 1. |
- Olai, H, et al.
(author)
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Protocol for meta-analysis of temperature reduction in animal models of cardiac arrest
- 2016
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In: Evidence-based preclinical medicine. - : Wiley. - 2054-703X. ; 3:1, s. 4-11
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Journal article (peer-reviewed)abstract
- Targeted temperature management (TTM) of 32-34 °C has been the standard treatment for out-of-hospital cardiac arrest since clinical trials in 2002 showed benefits to survival and neurological outcome. Recently, this treatment has been challenged by another clinical trial showing no difference in outcome between TTM of 33 °C and 36 °C. This protocol describes the methodology for a meta-analysis detailing temperature-reducing interventions to treat global ischaemia in animal models. By combining relevant data sets in the literature, we will explore the experimental evidence for TTM. Our aims are to explain possible translational gaps and provide methodological considerations for future experimental research and clinical trials.
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| 2. |
- Ahl, Matilda, et al.
(author)
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Physical Activity Reduces Epilepsy Incidence : a Retrospective Cohort Study in Swedish Cross-Country Skiers and an Experimental Study in Seizure-Prone Synapsin II Knockout Mice
- 2019
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In: Sports medicine - open. - : Springer. - 2199-1170 .- 2198-9761. ; 5:1
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Journal article (peer-reviewed)abstract
- BACKGROUND: Epilepsy patients commonly exercise less than the general population. Animal studies indicate beneficial effects of physical activity in established epilepsy, while its effect on the development is currently less known.METHODS: Here, we investigated the incidence of epilepsy during 20 years in a cohort of participants from the long-distance Swedish cross-country ski race Vasaloppet (n = 197,685) and compared it to the incidence of non-participating-matched controls included in the Swedish population register (n = 197,684). Individuals diagnosed with diseases such as stroke and epilepsy before entering the race were excluded from both groups. Experimentally, we also determined how physical activity could affect the development of epilepsy in epilepsy-prone synapsin II knockout mice (SynIIKO), with and without free access to a running wheel.RESULTS: We identified up to 40-50% lower incidence of epilepsy in the Vasaloppet participants of all ages before retirement. A lower incidence of epilepsy in Vasaloppet participants was seen regardless of gender, education and occupation level compared to controls. The participants included both elite and recreational skiers, and in a previous survey, they have reported a higher exercise rate than the general Swedish population. Sub-analyses revealed a significantly lower incidence of epilepsy in participants with a faster compared to slower finishing time. Dividing participants according to specified epilepsy diagnoses revealed 40-50% decrease in focal and unspecified epilepsy, respectively, but no differences in generalized epilepsy. Voluntary exercise in seizure-prone SynIIKO mice for 1 month before predicted epilepsy development decreased seizure manifestation from > 70 to 40%. Brain tissue analyses following 1 month of exercise showed increased hippocampal neurogenesis (DCX-positive cells), while microglial (Iba1) and astrocytic activation (GFAP), neuronal Map2, brain-derived neurotrophic factor and its receptor tyrosine receptor kinase B intensity were unaltered. Continued exercise for additionally 2 months after predicted seizure onset in SynIIKO mice resulted in a 5-fold reduction in seizure manifestation (from 90 to 20%), while 2 months of exercise initiated at the time of predicted seizure development gave no seizure relief, suggesting exercise-induced anti-epileptogenic rather than anti-convulsive effect.CONCLUSION: The clinical study and the experimental findings in mice indicate that physical activity may prevent or delay the development of epilepsy.
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| 3. |
- Bachiller, S., et al.
(author)
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Early-life stress elicits peripheral and brain immune activation differently in wild type and 5xFAD mice in a sex-specific manner
- 2022
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In: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 19
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Journal article (peer-reviewed)abstract
- BackgroundThe risk of developing Alzheimer’s disease (AD) is modulated by genetic and environmental factors. Early-life stress (ELS) exposure during critical periods of brain development can impact later brain function and health, including increasing the risk of developing AD. Microglial dysfunction and neuroinflammation have been implicated as playing a role in AD pathology and may be modulated by ELS. To complicate matters further, sex-specific effects have been noted in response to ELS and in the incidence and progression of AD.MethodsHere, we subjected male and female mice with either a wild type or 5xFAD familial AD-model background to maternal separation (MS) from postnatal day 2 to 14 to induce ELS.ResultsWe detected hippocampal neuroinflammatory alterations already at postnatal day 15. By 4 months of age, MS mice presented increased immobility time in the forced swim test and a lower discrimination index in the novel object recognition memory test compared to controls. We found altered Bdnf and Arc expression in the hippocampus and increased microglial activation in the prefrontal cortex due to MS in a sex-dependent manner. In 5xFAD mice specifically, MS exacerbated amyloid-beta deposition, particularly in females. In the periphery, the immune cell population was altered by MS exposure.ConclusionOverall, our results demonstrate that MS has both short- and long-term effects on brain regions related to memory and on the inflammatory system, both in the brain and periphery. These ELS-related effects that are detectable even in adulthood may exacerbate pathology and increase the risk of developing AD via sex-specific mechanisms.
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| 4. |
- Bachiller, S., et al.
(author)
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Maternal separation leads to regional hippocampal microglial activation and alters the behavior in the adolescence in a sex-specific manner
- 2020
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In: Brain, Behavior, & Immunity - Health. - : Elsevier BV. - 2666-3546. ; 9
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Journal article (peer-reviewed)abstract
- Early life adversities during childhood (such as maltreatment, abuse, neglect, or parental deprivation) may increase the vulnerability to cognitive disturbances and emotional disorders in both, adolescence and adulthood. Maternal separation (MS) is a widely used model to study stress-related changes in brain and behavior in rodents. In this study, we investigated the effect of MS (postnatal day 2–14, 3 h/day) in both, female and male adolescent mice. Specifically, we evaluated (i) the spatial working memory, anxiety and depressive-like behavior, (ii) the hippocampal synaptic gene expression, and (iii) the hippocampal neuroinflammatory response. Our results show that MS significantly increased depressive-like behavior in adolescent female mice and altered the spatial memory in adolescent male mice. In addition, MS led to decreased expression of genes related to synaptic function (5ht6r, Synaptophysin, and Cox-2) and induced an exacerbated microglial activation in dentate gyrus (DG), CA1, and CA3. However, while the levels of hippocampal inflammatory cytokines were not modified by MS, they did follow a sex-specific expression in adolescent mice. Taken together, our results suggest that MS induces long-term changes in hippocampal microglia and synaptic gene expression, alters the spatial memory, and induces depressive-like behavior in the adolescent mice, in a sex-specific manner.
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| 5. |
- Boza-Serrano, A., et al.
(author)
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Galectin-3 is elevated in CSF and is associated with A beta deposits and tau aggregates in brain tissue in Alzheimer's disease
- 2022
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In: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533.
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Journal article (peer-reviewed)abstract
- Galectin-3 (Gal-3) is a beta-galactosidase binding protein involved in microglial activation in the central nervous system (CNS). We previously demonstrated the crucial deleterious role of Gal-3 in microglial activation in Alzheimer's disease (AD). Under AD conditions, Gal-3 is primarily expressed by microglial cells clustered around A beta plaques in both human and mouse brain, and knocking out Gal-3 reduces AD pathology in AD-model mice. To further unravel the importance of Gal-3-associated inflammation in AD, we aimed to investigate the Gal-3 inflammatory response in the AD continuum. First, we measured Gal-3 levels in neocortical and hippocampal tissue from early-onset AD patients, including genetic and sporadic cases. We found that Gal-3 levels were significantly higher in both cortex and hippocampus in AD subjects. Immunohistochemistry revealed that Gal-3+ microglial cells were associated with amyloid plaques of a larger size and more irregular shape and with neurons containing tau-inclusions. We then analyzed the levels of Gal-3 in cerebrospinal fluid (CSF) from AD patients (n=119) compared to control individuals (n= 36). CSF Gal-3 levels were elevated in AD patients compared to controls and more strongly correlated with tau (p-Tau181 and t-tau) and synaptic markers (GAP-43 and neurogranin) than with amyloid-beta. Lastly, principal component analysis (PCA) of AD biomarkers revealed that CSF Gal-3 clustered and associated with other CSF neuroinflammatory markers, including sTREM-2, GFAP, and YKL-40. This neuroinflammatory component was more highly expressed in the CSF from amyloid-beta positive (A+), CSF p-Tau181 positive (T+), and biomarker neurodegeneration positive/negative (N+/-) (A + T +N+/-) groups compared to the A + T-N- group. Overall, Gal-3 stands out as a key pathological biomarker of AD pathology that is measurable in CSF and, therefore, a potential target for disease-modifying therapies involving the neuroinflammatory response.
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| 6. |
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| 7. |
- Garcia, M.g., et al.
(author)
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Maternal separation differentially modulates early pathology by sex in 5xFAD Alzheimer’s disease-transgenic mice
- 2023
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In: Brain, Behavior, & Immunity - Health. - 2666-3546. ; 32
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Journal article (peer-reviewed)abstract
- Alzheimer’s disease (AD) is the most common neurodegenerative disease. Most cases of AD are considered idiopathic and likely due to a combination of genetic, environmental, and lifestyle-related risk factors. Despite occurring decades before the typical age of an AD diagnosis, early-life stress (ELS) has been suggested to have long-lasting effects that may contribute to AD risk and pathogenesis. Still, the mechanisms that underlie the role of ELS on AD risk remain largely unknown. Here, we used 5xFAD transgenic mice to study relatively short-term alterations related to ELS in an AD-like susceptible mouse model at 6 weeks of age. To model ELS, we separated pups from their dams for 3 h per day from postnatal day 2–14. Around 6 weeks of age, we found that maternally separated (MS) 5xFAD mice, particularly female mice, displayed increased amyloid-β-immunoreactivity in the anterior cingulate cortex (ACC) and basolateral amygdala (BLA). In anterior cingulate cortex, we also noted significantly increased intraneuronal amyloid-β-immunoreactivity associated with MS but only in female mice. Moreover, IBA1-positive DAPI density was significantly increased in relation to MS in ACC and BLA, and microglia in BLA of MS mice had significantly different morphology compared to microglia in non-MS 5xFAD mice. Cytokine analysis showed that male MS mice, specifically, had increased levels of neuroinflammatory markers CXCL1 and IL-10 in hippocampal extracts compared to non-MS counterparts. Additionally, hippocampal extracts from both male and female MS 5xFAD mice had decreased levels of synapse- and activity-related markers Bdnf, 5htr6, Cox2, and Syp in hippocampus. Lastly, we performed behavioral tests to evaluate anxiety- and depressive-like behavior and working memory but could not detect any significant differences between groups. Overall, we detected several sex-specific molecular and cellular alterations in 6-week-old adolescent 5xFAD mice associated with MS that may help explain the connection between ELS and AD risk.
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| 8. |
- Gredal, H., et al.
(author)
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Diagnosis and long-term outcome in dogs with acute onset intracranial signs
- 2020
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In: Journal of Small Animal Practice. - : Wiley. - 0022-4510 .- 1748-5827. ; 61:2, s. 101-109
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Journal article (peer-reviewed)abstract
- Objectives: To investigate dogs with acute onset of intracranial signs suspected of stroke by primary veterinary clinicians, and establish possible differential diagnoses and long-term outcome. In addition, serum C-reactive protein and plasma cytokines were investigated as potential biomarkers of disease. Materials and Methods: All cases were evaluated by neurologic examination, routine haematology and biochemistry and measurement of serum C-reactive protein, plasma cytokine concentrations (interleukin-2, -6, -8, -10, tumour necrosis factor) and low-field MRI. Results: Primary veterinarians contacted the investigators with 85 suspected stroke cases. Only 20 met the inclusion criteria. Of these, two were diagnosed with ischaemic stroke. Other causes were idiopathic vestibular syndrome (n=6), brain tumour (n=5) and inflammatory brain disease (n=2); in five cases a precise diagnosis could not be determined. Median survival times were: brain tumour, 3 days, idiopathic vestibular syndrome, 315 days, ischaemic stroke, 365 days and inflammatory central nervous system (CNS) disease, 468 days. The median plasma concentrations of interleukin-2, -6, -8, -10 or tumour necrosis factor were not significantly increased in any of the diagnosis groups compared to healthy controls. Serum C-reactive protein was higher in dogs with brain tumours and inflammatory brain disease but not above the upper bound of the reference interval. Clinical Significance: Dogs that present with acute onset intracranial disease may have ischaemic stroke but are more likely to have other causes. Many dogs with such acute onset of neurological dysfunction (brain tumours excluded) may recover within a couple of weeks despite their initial severe clinical appearance.
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| 9. |
- Kovacs, Katalin T., et al.
(author)
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Change in autoantibody and cytokine responses during the evolution of neuromyelitis optica in patients with systemic lupus erythematosus : A preliminary study
- 2016
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In: Multiple Sclerosis Journal. - : SAGE Publications. - 1352-4585 .- 1477-0970. ; 22:9, s. 1192-1201
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Journal article (peer-reviewed)abstract
- Background: Neuromyelitis optica (NMO)-systemic lupus erythematosus (SLE) association is a rare condition characterized by multiple autoantibodies. Objective: To examine if, during the evolution of NMO, anti-AQP4 responses are part of polyclonal B cell activation, and if T cell responses contribute. Methods: In 19 samples of six patients who developed NMO during SLE, we examined the correlation of AQP4-IgG1 and IgM with (i) anti-MOG IgG and IgM, (ii) anti-nuclear, anti-nucleosome and anti-dsDNA IgG antibodies, (iii) cytokines and chemokines in the serum and (iv) longitudinal relation to NMO relapses/remission. Results: AQP4-IgG1 was present 1-2-5 years before the first NMO relapse. During relapse, AQP4-IgG1, ANA, anti-dsDNA and anti-nucleosome antibodies were elevated. Anti-MOG IgG/IgM and AQP4-IgM antibodies were not detected. AQP4-IgG1 antibodies correlated with concentration of anti-nucleosome, IFN-γ,interferon-gamma-induced CCL10/IP-10 and CCL17/TARC (p
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| 10. |
- Martinsson, I, et al.
(author)
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Aβ/APP-induced hyperexcitability and dysregulation of homeostatic synaptic plasticity in models of Alzheimer’s disease
- 2022
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Other publication (other academic/artistic)abstract
- The proper function of the nervous system is dependent on the appropriate timing of neuronal firing. Synapses continually undergo rapid activity-dependent modifications that require feedback mechanisms to maintain network activity within a window in which communication is energy efficient and meaningful. Homeostatic synaptic plasticity (HSP) and homeostatic intrinsic plasticity (HIP) are such negative feedback mechanisms. Accumulating evidence implicates that Alzheimer’s disease (AD)-related amyloid precursor protein (APP) and its cleavage product amyloid-beta (Aβ) play a role in the regulation of neuronal network activity, and in particular HSP. AD features impaired neuronal activity with regional early hyper-activity and Aβ-dependent hyperexcitability has also been demonstrated in AD transgenic mice. We demonstrate similar hyper-activity in AD transgenic neurons in culture that have elevated levels of both human APP and Aβ. To examine the individual roles of APP and Aβ in promoting hyperexcitability we used an APP construct that does not generate Aβ, or elevated Aβ levels independently of APP. Increasing either APP or Aβ in wild type (WT) neurons leads to increased frequency and amplitude of calcium transients. Since HSP/HIP mechanisms normally maintain a setpoint of activity, we examined whether homeostatic synaptic/intrinsic plasticity was altered in AD transgenic neurons. Using methods known to induce HSP/HIP, we demonstrate that APP protein levels are regulated by chronic modulation of activity and show that AD transgenic neurons have an impaired response to global changes in activity. Further, AD transgenic compared to WT neurons failed to adjust the length of their axon initial segments (AIS), an adaptation known to alter excitability. Thus, we present evidence that both APP and Aβ influence neuronal activity and that mechanisms of HSP/HIP are disrupted in neuronal models of AD.Competing Interest StatementThe authors have declared no competing interest.
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