| 1. |
- Almeida, Francisco C., et al.
(författare)
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APOE genotype dictates lipidomic signatures in primary human hepatocytes
- 2024
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Ingår i: Journal of Lipid Research. - 0022-2275 .- 1539-7262. ; 65:2
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Tidskriftsartikel (refereegranskat)abstract
- Apolipoprotein E (APOE) genetic variants are most notably known for their divergent impact on the risk of developing Alzheimer's disease. While APOE genotype has been consistently shown to modulate lipid metabolism in a variety of cellular contexts, the effect of APOE alleles on the lipidome in hepatocytes is unknown. In this study, we investigated the contribution of APOE alleles to lipidomic profiles of donor -derived primary human hepatocytes from 77 subjects. Lipidomic data obtained by liquid chromatography -mass spectrometry were analyzed across e2/e3, e3/e3, and e3/e4 genotypes to reveal how APOE modulates lipid relative levels over age and between groups. Hepatic APOE concentration, measured by ELISA, was assessed for correlation with lipid abundance in subjects grouped as per APOE genotype and sex. APOE genotype -specific differential lipidomic signatures associated with age for multiple lipid classes but did not differ between sexes. Compared to e2/e3, e3/e4 hepatocytes had higher abundance of acylcarnitines (AC) and acylphosphatidylglycerol (AcylPG) as a class, as well as higher medium and long -chain ACs, AcylPG, phosphatidylglycerol (PG), bis(monoacylglycerol)phosphate (BMP), monoacylglycerol (MG) and diacylglycerol (DG) species. The e3/e4 hepatocytes also exhibited a higher abundance of medium and long -chain ACs compared to the e3/e3 hepatocytes. Only in the e3/e4 hepatocytes, APOE concentration was lower and showed a negative correlation with BMP levels, specifically in females. APOE genotype dictates a differential lipidome in primary human hepatocytes. The lipids involved suggest mitochondrial dysfunction with accompanying alterations in neutral lipid storage, reflective of a general disturbance of free fatty acid metabolism in human hepatocytes with the e4 allele.
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| 2. |
- Andersson, Lisa, et al.
(författare)
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Mutations in DMRT3 affect locomotion in horses and spinal circuit function in mice
- 2012
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 488:7413, s. 642-646
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Tidskriftsartikel (refereegranskat)abstract
- Locomotion in mammals relies on a central pattern-generating circuitry of spinal interneurons established during development that coordinates limb movement(1). These networks produce left-right alternation of limbs as well as coordinated activation of flexor and extensor muscles(2). Here we show that a premature stop codon in the DMRT3 gene has a major effect on the pattern of locomotion in horses. The mutation is permissive for the ability to perform alternate gaits and has a favourable effect on harness racing performance. Examination of wild-type and Dmrt3-null mice demonstrates that Dmrt3 is expressed in the dI6 subdivision of spinal cord neurons, takes part in neuronal specification within this subdivision, and is critical for the normal development of a coordinated locomotor network controlling limb movements. Our discovery positions Dmrt3 in a pivotal role for configuring the spinal circuits controlling stride in vertebrates. The DMRT3 mutation has had a major effect on the diversification of the domestic horse, as the altered gait characteristics of a number of breeds apparently require this mutation.
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| 3. |
- Edlund, Anna, 1983-, et al.
(författare)
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Elucidating the effects of a high fat diet on markers of brain insulin signaling, gliosis and synaptic integrity in mice with humanized APOEε3
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Mid-life obesity is associated with an increased risk of dementia, including Alzheimer’s disease (AD). Elevated circulating free fatty acids were previously shown tohamper insulin transport across the blood-brain barrier (BBB) and dysfunctional brain insulin signaling in turn negatively affects cognition by modulating excitatory synapses. Addressing links between diet, lipid metabolism and cognition in vivo is complicated by species-specific differences in lipid metabolism. Here we used FRGN mice with humanized livers of the AD risk-neutral APOEε3/ε3 genotype to explore the effects of a high-fat diet (HFD) on markers of insulin signaling, gliosis and synaptic integrity in the brain.Methods: FRGN mice (n=11) with humanized livers of the APOEε3/ε3 genotype were fed normal chow (n=3) versus a HFD for 12 (n=5) or 20 weeks (n=3). Brain cortical and hippocampal tissues were biochemically analysed for changes in markers of gliosis, synaptic integrity, glucose transporters and insulin signaling. Immunohistochemistry (IHC) was used to assess whether the identified changes replicated at the histological level.Results: Humanization of the mouse liver produced human-like levels of plasma apolipoprotein B and low-density lipoprotein, which were further increased by a 12 week HFD. Mice on the HFD exhibited increased phosphorylation of the insulin receptor substrate 1 (IRS-1) at Ser-616, previously linked to brain insulin resistance, in parallel with reduced cortical marker levels of synaptic AMPAR. Markers of hippocampal insulin signaling were unaffected by the HFD however we observed an increase in the astrocytic marker GFAP but not the microglia- associated IBA1, and intracellular apolipoprotein E (apoE) levels alongside altered levels of the postsynaptic AMPA receptors and PSD-95. Hippocampal and cortical marker levels of the pre-synaptic synaptophysin were increased. The observed changes in the brain tissues were subtle and only alterations in the synaptophysin levels were corroborated using IHC.Conclusions: Our findings suggest that a HFD alters insulin signaling specifically in the cortex, and the levels of AMPAR, PSD-95, synaptophysin and apoE in the brains of FRGN mice with humanized livers, in the absence of microglia activation. These findings support a key role of the diet in brain health with implications for diseases like AD.
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| 4. |
- Edlund, Anna K., et al.
(författare)
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Impact of high-fat diet on brain integrity in APOEε3 humanized liver mice
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Mid-life obesity and dysfunctional brain insulin signaling are associated with an increased risk of dementia. We used FRGN mice (n=11) with humanized APOEε3/ε3 livers to explore the effects of a high-fat-diet (HFD) on markers of insulin signaling, gliosis and synaptic integrityin brain cortical and hippocampal tissues using western blotting and immunohistochemistry.Humanization of the mouse liver produced human-like levels of plasma apolipoprotein B and low-density lipoprotein, which were increased by a 12 week HFD. Mice on the HFD exhibitedincreased phosphorylation of insulin receptor substrate 1 (IRS-1-Ser612) and reduced cortical levels of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). Hippocampal insulin signaling markers were unaffected but the astrocytic marker glial fibrillary acidic protein (GFAP), apolipoprotein E (apoE) and synatophysin were elevated alongsidealtered levels of AMPAR. Our results acquired in a humanized liver mouse model support a key role of the diet in brain health, with implications for diseases like AD.
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| 5. |
- Giannisis,, Andreas, et al.
(författare)
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Brain integrity is altered by hepatic APOEε4 in humanized-liver mice
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Liver-generated plasma apolipoprotein E (apoE) does not enter the brain but nonetheless correlates with Alzheimer’s disease (AD) risk and AD biomarker levels. Carriers of APOEε4, the strongest genetic AD risk factor, exhibit lower plasma apoE and altered brain integrity already at mid-life versus non-APOEε4 carriers. Whether altered plasma liver-derived apoE or specifically an APOEε4 liver phenotype promotes brain injury and neurodegeneration is unknown. Here we investigated the brains of Fah-/-, Rag2-/-, Il2rg-/- mice on the Non-Obese Diabetic (NOD) background (FRGN) with humanized-livers of an AD risk-associated APOE ε4/ε4 versus an APOE ε2/ε3 genotype. Reduced endogenous mouse apoE levels in the brains of APOE ε4/ε4 liver mice were accompanied by various changes in markers of synaptic integrity, neuroinflammation, and insulin signaling. Plasma apoE4 levels were associated with unfavorable changes in several of the assessed markers. These results propose a previously unexplored role of the liver in the APOEε4-associated risk neurodegenerative diseases.
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| 6. |
- Giannisis, Andreas, et al.
(författare)
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Brain integrity is altered by hepatic APOE ε4 in humanized-liver mice
- 2022
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 27:8, s. 3533-3543
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Tidskriftsartikel (refereegranskat)abstract
- Liver-generated plasma apolipoprotein E (apoE) does not enter the brain but nonetheless correlates with Alzheimer’s disease (AD) risk and AD biomarker levels. Carriers of APOEε4, the strongest genetic AD risk factor, exhibit lower plasma apoE and altered brain integrity already at mid-life versus non-APOEε4 carriers. Whether altered plasma liver-derived apoE or specifically an APOEε4 liver phenotype promotes neurodegeneration is unknown. Here we investigated the brains of Fah−/−, Rag2−/−, Il2rg−/− mice on the Non-Obese Diabetic (NOD) background (FRGN) with humanized-livers of an AD risk-associated APOE ε4/ε4 versus an APOE ε2/ε3 genotype. Reduced endogenous mouse apoE levels in the brains of APOE ε4/ε4 liver mice were accompanied by various changes in markers of synaptic integrity, neuroinflammation and insulin signaling. Plasma apoE4 levels were associated with unfavorable changes in several of the assessed markers. These results propose a previously unexplored role of the liver in the APOEε4-associated risk of neurodegenerative disease.
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| 7. |
- Giannisis, Andreas, et al.
(författare)
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Plasma apolipoprotein E levels in longitudinally followed patients with mild cognitive impairment and Alzheimer's disease
- 2022
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Ingår i: Alzheimer's Research & Therapy. - : BioMed Central (BMC). - 1758-9193. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Low levels of plasma apolipoprotein E (apoE) and presence of the APOE epsilon 4 allele are associated with an increased risk of Alzheimer's disease (AD). Although the increased risk of AD in APOE epsilon 4-carriers is well-established, the protein levels have received limited attention. Methods: We here report the total plasma apoE and apoE isoform levels at baseline from a longitudinally (24 months) followed cohort including controls (n = 3 9), patients with stable amnestic mild cognitive impairment during 24 months follow up (MCI-MCI, n = 3 0) , patients with amnestic MCI (aMCI) that during follow-up were clinically diagnosed with AD with dementia (ADD) (MCI-ADD, n = 28), and patients with AD with dementia (ADD) at baseline (ADD, n = 28). We furthermore assessed associations between plasma apoE levels with cerebrospinal fluid (CSF) AD biomarkers and alpha-synuclein, as well as both CSF and plasma neurofilament light chain (NfL), YKL-40 and kallikrein 6. Results: Irrespective of clinical diagnosis, the highest versus the lowest apoE levels were found in APOE epsilon 2/epsilon 3 versus APOE epsilon 4/epsilon 4 subjects, with the most prominent differences exhibited in females. Total plasma apoE levels were 32% and 21% higher in the controls versus MCI-ADD and ADD patients, respectively. Interestingly, MCI-ADD patients exhibited a 30% reduction in plasma apoE compared to MCI-MCI patients. This decrease appeared to be associated with brain amyloid-beta (A beta(42)) pathology regardless of disease status as assessed using the Amyloid, Tau, and Neurodegeneration (A/T/N) classification. In addition to the association between low plasma apoE and low levels of CSF A beta(42), lower apoE levels were also related to higher levels of CSF total tau (t-tau) and tau phosphorylated at Threonine 181 residue (p-tau) and NfL as well as a worse performance on the mini-mental-state-examination. In MCI-ADD patients, low levels of plasma apoE were associated with higher levels of CSF alpha-synuclein and kallikrein 6. No significant correlations between plasma apoE and the astrocytic inflammatory marker YKL40 were observed. Conclusions: Our results demonstrate important associations between low plasma apoE levels, A beta pathology, and progression from aMCI to a clinical ADD diagnosis.
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| 8. |
- Hanell, Anders, et al.
(författare)
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Functional and Histological Outcome after Focal Traumatic Brain Injury Is Not Improved in Conditional EphA4 Knockout Mice
- 2012
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Ingår i: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 0897-7151 .- 1557-9042. ; 29:17, s. 2660-2671
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the role of the axon guidance molecule EphA4 following traumatic brain injury (TBI) in mice. Neutralization of EphA4 improved motor function and axonal regeneration following experimental spinal cord injury (SCI). We hypothesized that genetic absence of EphA4 could improve functional and histological outcome following TBI. Using qRT-PCR in wild-type (WT) mice, we evaluated the EphA4 mRNA levels following controlled cortical impact (CCI) TBI or sham injury and found it to be downregulated in the hippocampus (p < 0.05) but not the cortex ipsilateral to the injury at 24 h post-injury. Next, we evaluated the behavioral and histological outcome following CCI using WT mice and Emx1-Cre-driven conditional knockout (cKO) mice. In cKO mice, EphA4 was completely absent in the hippocampus and markedly reduced in the cortical regions from embryonic day 16, which was confirmed using Western blot analysis. EphA4 cKO mice had similar learning and memory abilities at 3 weeks post-TBI compared to WT controls, although brain-injured animals performed worse than sham-injured controls (p < 0.05). EphA4 cKO mice performed similarly to WT mice in the rotarod and cylinder tests of motor function up to 29 days post-injury. TBI increased cortical and hippocampal astrocytosis (GFAP immunohistochemistry, p < 0.05) and hippocampal sprouting (Timm stain, p < 0.05) and induced a marked loss of hemispheric tissue (p < 0.05). EphA4 cKO did not alter the histological outcome. Although our results may argue against a beneficial role for EphA4 in the recovery process following TBI, further studies including post-injury pharmacological neutralization of EphA4 are needed to define the role for EphA4 following TBI.
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| 9. |
- Larhammar, Martin, 1985-, et al.
(författare)
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SLC10A4 Is a Vesicular Amine-Associated Transporter Modulating Dopamine Homeostasis
- 2015
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 77:6, s. 526-536
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe neuromodulatory transmitters, biogenic amines, have profound effects on multiple neurons and are essential for normal behavior and mental health. Here we report that the orphan transporter SLC10A4, which in the brain is exclusively expressed in presynaptic vesicles of monoaminergic and cholinergic neurons, has a regulatory role in dopamine homeostasis.MethodsWe used a combination of molecular and behavioral analyses, pharmacology, and in vivo amperometry to assess the role of SLC10A4 in dopamine-regulated behaviors.ResultsWe show that SLC10A4 is localized on the same synaptic vesicles as either vesicular acetylcholine transporter or vesicular monoamine transporter 2. We did not find evidence for direct transport of dopamine by SLC10A4; however, synaptic vesicle preparations lacking SLC10A4 showed decreased dopamine vesicular uptake efficiency. Furthermore, we observed an increased acidification in synaptic vesicles isolated from mice overexpressing SLC10A4. Loss of SLC10A4 in mice resulted in reduced striatal serotonin, noradrenaline, and dopamine concentrations and a significantly higher dopamine turnover ratio. Absence of SLC10A4 led to slower dopamine clearance rates in vivo, which resulted in accumulation of extracellular dopamine. Finally, whereas SLC10A4 null mutant mice were slightly hypoactive, they displayed hypersensitivity to administration of amphetamine and tranylcypromine.ConclusionsOur results demonstrate that SLC10A4 is a vesicular monoaminergic and cholinergic associated transporter that is important for dopamine homeostasis and neuromodulation in vivo. The discovery of SLC10A4 and its role in dopaminergic signaling reveals a novel mechanism for neuromodulation and represents an unexplored target for the treatment of neurological and mental disorders.
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| 10. |
- Leão, Richardson Naves, et al.
(författare)
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OLM interneurons differentially modulate CA3 and entorhinal inputs to hippocampal CA1 neurons
- 2012
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Ingår i: Nature Neuroscience. - : Springer Science and Business Media LLC. - 1097-6256 .- 1546-1726. ; 15:11, s. 1524-1530
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Tidskriftsartikel (refereegranskat)abstract
- The vast diversity of GABAergic interneurons is believed to endow hippocampal microcircuits with the required flexibility for memory encoding and retrieval. However, dissection of the functional roles of defined interneuron types has been hampered by the lack of cell-specific tools. We identified a precise molecular marker for a population of hippocampal GABAergic interneurons known as oriens lacunosum-moleculare (OLM) cells. By combining transgenic mice and optogenetic tools, we found that OLM cells are important for gating the information flow in CA1, facilitating the transmission of intrahippocampal information (from CA3) while reducing the influence of extrahippocampal inputs (from the entorhinal cortex). Furthermore, we found that OLM cells were interconnected by gap junctions, received direct cholinergic inputs from subcortical afferents and accounted for the effect of nicotine on synaptic plasticity of the Schaffer collateral pathway. Our results suggest that acetylcholine acting through OLM cells can control the mnemonic processes executed by the hippocampus.
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| 11. |
- Meunier, Dominique, et al.
(författare)
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Expression Analysis of Proline Rich 15 (Prr15) in Mouse and Human Gastrointestinal Tumors
- 2011
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Ingår i: Molecular Carcinogenesis. - : Wiley. - 0899-1987 .- 1098-2744. ; 50:1, s. 8-15
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Tidskriftsartikel (refereegranskat)abstract
- Proline rich 15 (Prr15), which encodes a protein of unknown function, is expressed almost exclusively in postmitotic cells both during fetal development and in adult tissues, such as the intestinal epithelium and the testis. To determine if this specific expression is lost in intestinal neoplasias, we examined Prr15 expression by in situ hybridization (ISH) on mouse intestinal tumors caused by different gene mutations, and on human colorectal cancer (CRC) samples. Prr15/PRR15 expression was consistently observed in mouse gastrointestinal (GI) tumors caused by mutations in the Apc gene, as well as in several advanced stage human CRCs. In contrast, no Prr15 expression was detected in intestinal tumors derived from mice carrying mutations in the Smad3, Smad4, or Cdkn1b genes. These findings, combined with the fact that a majority of sporadic human CRCs carry APC mutations, strongly suggest that the expression of Prr15/PRR15 in mouse and human GI tumors is linked, directly or indirectly, to the absence of the APC protein or, more generally, to the disruption of the Wnt signaling pathway.
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| 12. |
- Motallebipour, Mehdi, et al.
(författare)
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Differential binding and co-binding pattern of FOXA1 and FOXA3 and their relation to H3K4me3 in HepG2 cells revealed by ChIP-seq
- 2009
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 10:11, s. R129-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The forkhead box/winged helix family members FOXA1, FOXA2, and FOXA3 are of high importance in development and specification of the hepatic linage and the continued expression of liver-specific genes. RESULTS: Here, we present a genome-wide location analysis of FOXA1 and FOXA3 binding sites in HepG2 cells through chromatin immunoprecipitation with detection by sequencing (ChIP-seq) studies and compare these with our previous results on FOXA2. We found that these factors often bind close to each other in different combinations and consecutive immunoprecipitation of chromatin for one and then a second factor (ChIP-reChIP) shows that this occurs in the same cell and on the same DNA molecule, suggestive of molecular interactions. Using co-immunoprecipitation, we further show that FOXA2 interacts with both FOXA1 and FOXA3 in vivo, while FOXA1 and FOXA3 do not appear to interact. Additionally, we detected diverse patterns of trimethylation of lysine 4 on histone H3 (H3K4me3) at transcriptional start sites and directionality of this modification at FOXA binding sites. Using the sequence reads at polymorphic positions, we were able to predict allele specific binding for FOXA1, FOXA3, and H3K4me3. Finally, several SNPs associated with diseases and quantitative traits were located in the enriched regions. CONCLUSIONS: We find that ChIP-seq can be used not only to create gene regulatory maps but also to predict molecular interactions and to inform on the mechanisms for common quantitative variation.
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| 13. |
- Natarajan, Karthick, et al.
(författare)
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Single-cell multimodal analysis in a case with reduced penetrance of Progranulin-Frontotemporal Dementia
- 2021
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Ingår i: Acta neuropathologica communications. - : BioMed Central (BMC). - 2051-5960. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- We identified an autosomal dominant progranulin mutation carrier without symptoms of dementia in her lifetime (Reduced Penetrance Mutation Carrier, RedPenMC). This resistance to develop expected pathology presents a unique opportunity to interrogate neurodegenerative mechanisms. We performed multimodal single-nuclei analyses of post-mortem frontal cortex from RedPenMC, including transcriptomics and global levels of chromatin marks. RedPenMC had an increased ratio of GRN-expressing microglia, higher levels of activating histone mark H3k4me3 in microglia and lower levels of the repressive chromatin marks H3k9me1 and H3k9me3 in the frontal cortex than her affected mutation carrier son and evidence of higher protein levels of progranulin in both plasma and brain homogenates. Although the study is limited to one case, the results support that restoring brain progranulin levels may be sufficient to escape neurodegeneration and FTD. In addition to previously identified modifier genes, it is possible that epigenetic marks may contribute to the increased progranulin expression in cases of reduced penetrance. These findings may stimulate similar follow-up studies and new therapeutic approaches.
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| 14. |
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| 15. |
- Patra, Kalicharan, et al.
(författare)
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A role for solute carrier family 10 member 4, or vesicular aminergic-associated transporter, in structural remodelling and transmitter release at the mouse neuromuscular junction.
- 2015
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Ingår i: European Journal of Neuroscience. - : Wiley. - 0953-816X .- 1460-9568. ; 41:3, s. 316-327
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Tidskriftsartikel (refereegranskat)abstract
- The solute carrier and presynaptic vesicle protein solute carrier family 10 member 4, or vesicular aminergic-associated transporter (VAAT), was recently proven to have a modulatory role in central cholinergic signalling. It is currently unknown whether VAAT also affects peripheral cholinergic synapses. Here we demonstrated a regulatory role for the presynaptic vesicle protein VAAT in neuromuscular junction (NMJ) development and function. NMJs lacking VAAT had fewer branch points, whereas endplates showed an increased number of islands. Whereas the amplitude of spontaneous miniature endplate potentials in VAAT-deficient NMJs was decreased, the amplitude of evoked endplate potentials and the size of the readily releasable pool of vesicles were both increased. Moreover, VAAT-deficient NMJs displayed aberrant short-term synaptic plasticity with enhanced synaptic depression in response to high-frequency stimulation. Finally, the transcript levels of cholinergic receptor subunits in VAAT-deficient muscles were increased, indicating a compensatory postsynaptic sensitization. Our results suggested that VAAT modulates NMJ transmission efficiency and, as such, may represent a novel target for treatment of disorders affecting motor neurons.
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| 16. |
- Patra, Kalicharan, et al.
(författare)
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Assessment of kallikrein 6 as a cross-sectional and longitudinal biomarker for Alzheimer's disease
- 2018
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Ingår i: Alzheimer's Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Kallikrein 6 (KLK6) is known to be an age-related protease expressed at high levels in the central nervous system. It was previously shown to be involved in proteolysis of extracellular proteins implicated in neurodegenerative diseases such as Alzheimer's disease (AD), prompting validation of KLK6 as a potential biomarker of disease. However, analyses of both plasma and cerebrospinal fluid (CSF) levels of KLK6 in patients with AD have been inconclusive. We present a detailed analysis of KLK6 in plasma and CSF in two separate cohorts in a cross-sectional and a longitudinal clinical setting. Methods: The cross-sectional cohort included control subjects without dementia and patients with AD, and the longitudinal cohort included patients with MCI and patients with AD followed over a 2-year period. Plasma and CSF levels of KLK6 were quantified by use of a previously developed and validated enzyme-linked immunosorbent assay. Statistical analyses were performed to compare KLK6 levels between diagnostic groups and to identify potential associations between KLK6 level, age, apolipoprotein E (APOE) genotype, total apoE level and the classical CSF AD biomarkers. Results: In the cross-sectional setting, KLK6 levels in plasma but not in CSF were significantly higher in the AD group than in control subjects. CSF but not plasma KLK6 levels were positively correlated with age in both the cross-sectional and longitudinal settings. In both cohorts, the CSF KLK6 levels were significantly and positively correlated with the CSF levels of core AD biomarkers. Total plasma and CSF apoE levels were positively associated with KLK6 in the cross-sectional study. Finally, during the 2-year monitoring period of the longitudinal cohort, CSF KLK6 levels increased with disease progression over time in the investigated patient groups. Conclusions: In two separate cohorts we have confirmed the previously reported correlation between age and CSF levels of KLK6. Increased plasma KLK6 levels in patients with AD with a more advanced disease stage suggest KLK6 as a potential biomarker in patients with AD with more severe dementia. Significant correlations between KLK6 levels and core CSF AD biomarkers suggest molecular links between KLK6 and AD-related pathological processes.
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| 17. |
- Patra, Kalicharan
(författare)
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Modulation of Neuronal Functions : the Role of SLC10A4
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Mental health of a person depends on the correct functioning of the brain. The brain and the spinal cord contain many types of cells, of which one important type are called the neurons. Neurons are special in the way they connect to each other to form large networks. The chemicals called transmitters are packed at the nerve endings into tiny packets called vesicles and when a signal arrives these vesicles fuse immediately to the attached cell surface and release their contents. The role of the synaptic vesicular transporter proteins is to ensure proper packing of transmitter molecules that can be released upon stimulation. Vesicular packing is an important process. The carrier proteins involved in packing work in coordination to determine the amount and type of transmitters to be packed. Missing a carrier protein from the vesicles might lead to improper packing and inaccurate signaliing. These signaling molecules are known for their implications in many psychiatric and neurological disorders like Alzheimer’s disease, Parkinson’s disease, Schizophrenia, and attention deficit to name just a few. How a vesicular transporter can affect the modulatory functions of aminergic neurons is the subject of this thesis. This thesis reports on the effects of the loss of a vesicular orphan transporter. Study I demonstrates the localization of this protein to monoaminergic and cholinergic terminals. It reports the effect of the loss of Slc10A4 on vesicular dopamine uptake, synaptic clearance of dopamine and hypersensitivity of animals to dopamine related psychostimulants. Study I also provides evidence for ATP as a possible ligand for SLC10A4 protein. Study II provides data on the clinical relevance of Slc10A4 in playing a protective role against vulnerability to epilepsy. It reports that loss of Slc10A4 renders the animals hypersensitive to cholinergic drugs. Study III provides a closer look at individual cholinergic synapses at neuromuscular junctions in mice lacking Slc10A4. The structural and electrophysiological properties of the NMJ are found compromised because of the loss of this vesicular protein. Taken together, this thesis presents a SV protein’s perspective of viewing at modulation of synaptic transmission.
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| 18. |
- Patra, Kalicharan, et al.
(författare)
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Plasma Apolipoprotein E Monomer and Dimer Profile and Relevance to Alzheimer's Disease
- 2019
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 71:4, s. 1217-1231
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Tidskriftsartikel (refereegranskat)abstract
- The APOE epsilon 4 gene variant is the strongest genetic risk factor for Alzheimer's disease (AD), whereas APOE epsilon 3 conventionally is considered as 'risk neutral' although APOE epsilon 3-carriers also develop AD. Previous studies have shown that the apolipoprotein E3 (apoE3) isoform occurs as monomers, homodimers and heterodimers with apolipoprotein A-II in human body fluids and brain tissue, but the relevance of a plasma apoE3 monomer/dimer profile to AD is unknown. Here we assessed the distribution of monomers, homodimers and heterodimers in plasma from control subjects and patients with mild cognitive impairment (MCI) and AD with either a homozygous APOE epsilon 3 (n = 31 control subjects, and n = 14 MCI versus n = 5 AD patients) or APOE epsilon 4 genotype (n = 1 control subject, n = 21 MCI and n = 7 AD patients). Total plasma apoE levels were lower in APOE epsilon 4-carriers and overall correlated significantly to CSF A beta(42), p(Thr181)-tau and t-tau levels. Apolipoprotein E dimers were only observed in the APOE epsilon 3-carriers and associated with total plasma apoE levels, negatively correlated to apoE monomers, but were unrelated to plasma homocysteine levels. Importantly, the APOE epsilon 3-carrying AD patients versus controls exhibited a significant decrease in apoE homodimers (17.8 +/- 9.6% versus 26.7 +/- 6.3%, p = 0.025) paralleled by an increase in apoE monomers (67.8 +/- 18.3% versus 48.5 +/- 11.2%, p = 0.008). In the controls, apoE monomers and heterodimers were significantly associated with plasma triglycerides; the apoE heterodimers were also associated with levels of high-density lipoprotein cholesterol. The physiological relevance of apoE dimer formation needs to be further investigated, though the distribution of apoE in monomers and dimers appears to be of relevance to AD in APOE epsilon 3 subjects.
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| 19. |
- Reinius, Björn, et al.
(författare)
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Conditional targeting of medium spiny neurons in the striatal matrix
- 2015
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Ingår i: Frontiers in Behavioral Neuroscience. - : Frontiers Media SA. - 1662-5153. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- The striatum serves as the main input to the basal ganglia, and is key for the regulation of motor behaviors, compulsion, addiction, and various cognitive and emotional states. Its deterioration is associated with degenerative disorders such as Huntington's disease. Despite its apparent anatomical uniformity, it consists of intermingled cell populations, which have precluded straightforward anatomical sub-classifications adhering to functional dissections. Approximately 95% of the striatal neurons are inhibitory projection neurons termed medium spiny neurons (MSNs). They are commonly classified according to their expression of either dopamine receptor D1 or D2, which also determines their axonal projection patterns constituting the direct and indirect pathway in the basal ganglia. lmmunohistochemical patterns have further indicated compartmentalization of the striatum to the striosomes and the surrounding matrix, which integrate MSNs of both the D1 and D2 type. Here, we present a transgenic mouse line, Gpr101-Cre, with Cre recombinase activity localized to matrix D1 and D2 MSNs. Using two Gpr101-Cre founder lines with different degrees of expression in the striatum, we conditionally deleted the vesicular inhibitory amino acid transporter (VIAAT), responsible for storage of GABA and glycine in synaptic vesicles. Partial ablation of VIAAT (in similar to 36% of MSNs) resulted in elevated locomotor activity compared to control mice, when provoked with the monoamine reuptake inhibitor cocaine. Near complete targeting of matrix MSNs led to profoundly changed motor behaviors, which increased in severity as the mice aged. Moreover, these mice had exaggerated muscle rigidity, retarded growth, increased rate of spontaneous deaths, and defective memory. Therefore, our data provide a link between dysfunctional GABA signaling of matrix MSNs to specific behavioral alterations, which are similar to the symptoms of Huntington's disease.
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| 20. |
- Twohig, Daniel, et al.
(författare)
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The relevance of cerebrospinal fluid α-synuclein levels to sporadic and familial Alzheimer's disease
- 2018
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Ingår i: Acta neuropathologica communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Accumulating evidence demonstrating higher cerebrospinal fluid (CSF) -synuclein (Syn) levels and Syn pathology in the brains of Alzheimer's disease (AD) patients suggests that Syn is involved in the pathophysiology of AD. To investigate whether Syn could be related to specific aspects of the pathophysiology present in both sporadic and familial disease, we quantified CSF levels of Syn and assessed links to various disease parameters in a longitudinally followed cohort (n=136) including patients with sporadic mild cognitive impairment (MCI) and AD, and in a cross-sectional sample from the Dominantly Inherited Alzheimer's Network (n=142) including participants carrying autosomal dominant AD (ADAD) gene mutations and their non-mutation carrying family members.Our results show that sporadic MCI patients that developed AD over a period of two years exhibited higher baseline Syn levels (p=0.03), which inversely correlated to their Mini-Mental State Examination scores, compared to cognitively normal controls (p=0.02). In the same patients, there was a dose-dependent positive association between CSF Syn and the APOE epsilon 4 allele. Further, CSF Syn levels were higher in symptomatic ADAD mutation carriers versus non-mutation carriers (p=0.03), and positively correlated to the estimated years from symptom onset (p=0.05) across all mutation carriers. In asymptomatic (Clinical Dementia Rating<0.5) PET amyloid-positive ADAD mutation carriers CSF Syn was positively correlated to C-11-Pittsburgh Compound-B (PiB) retention in several brain regions including the posterior cingulate, superior temporal and frontal cortical areas. Importantly, APOE epsilon 4-positive ADAD mutation carriers exhibited an association between CSF Syn levels and mean cortical PiB retention (p=0.032). In both the sporadic AD and ADAD cohorts we found several associations predominantly between CSF levels of Syn, tau and amyloid-(1-40).Our results suggest that higher CSF Syn levels are linked to AD pathophysiology at the early stages of disease development and to the onset of cognitive symptoms in both sporadic and autosomal dominant AD. We conclude that APOE epsilon 4 may promote the processes driven by Syn, which in turn may reflect on molecular mechanisms linked to the asymptomatic build-up of amyloid plaque burden in brain regions involved in the early stages of AD development.
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| 21. |
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| 22. |
- Wallerman, Ola, et al.
(författare)
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Molecular interactions between HNF4a, FOXA2 and GABP identified at regulatory DNA elements through ChIP-sequencing
- 2009
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 37:22, s. 7498-7508
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Tidskriftsartikel (refereegranskat)abstract
- Gene expression is regulated by combinations of transcription factors, which can be mapped to regulatory elements on a genome-wide scale using ChIP experiments. In a previous ChIP-chip study of USF1 and USF2 we found evidence also of binding of GABP, FOXA2 and HNF4a within the enriched regions. Here, we have applied ChIP-seq for these transcription factors and identified 3064 peaks of enrichment for GABP, 7266 for FOXA2 and 18783 for HNF4a. Distal elements with USF2 signal was frequently bound also by HNF4a and FOXA2. GABP peaks were found at transcription start sites, whereas 94% of FOXA2 and 90% of HNF4a peaks were located at other positions. We developed a method to accurately define TFBS within peaks, and found the predicted sites to have an elevated conservation level compared to peak centers; however the majority of bindings were not evolutionary conserved. An interaction between HNF4a and GABP was seen at TSS, with one-third of the HNF4a positive promoters being bound also by GABP, and this interaction was verified by co-immunoprecipitations.
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| 23. |
- Wootz, Hanna, et al.
(författare)
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Alterations in the motor neuron-renshaw cell circuit in the Sod1(G93A) mouse model
- 2013
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Ingår i: Journal of Comparative Neurology. - : Wiley. - 0021-9967 .- 1096-9861. ; 521:7, s. 1449-1469
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Tidskriftsartikel (refereegranskat)abstract
- Motor neurons become hyperexcitable during progression of amyotrophic lateral sclerosis (ALS). This abnormal firing behavior has been explained by changes in their membrane properties, but more recently it has been suggested that changes in premotor circuits may also contribute to this abnormal activity. The specific circuits that may be altered during development of ALS have not been investigated. Here we examined the Renshaw cell recurrent circuit that exerts inhibitory feedback control on motor neuron firing. Using two markers for Renshaw cells (calbindin and cholinergic nicotinic receptor subunit alpha2 [Chrna2]), two general markers for motor neurons (NeuN and vesicular acethylcholine transporter [VAChT]), and two markers for fast motor neurons (Chondrolectin and calcitonin-related polypeptide alpha [Calca]), we analyzed the survival and connectivity of these cells during disease progression in the Sod1G93A mouse model. Most calbindin-immunoreactive (IR) Renshaw cells survive to end stage but downregulate postsynaptic Chrna2 in presymptomatic animals. In motor neurons, some markers are downregulated early (NeuN, VAChT, Chondrolectin) and others at end stage (Calca). Early downregulation of presynaptic VAChT and Chrna2 was correlated with disconnection from Renshaw cells as well as major structural abnormalities of motor axon synapses inside the spinal cord. Renshaw cell synapses on motor neurons underwent more complex changes, including transitional sprouting preferentially over remaining NeuN-IR motor neurons. We conclude that the loss of presynaptic motor axon input on Renshaw cells occurs at early stages of ALS and disconnects the recurrent inhibitory circuit, presumably resulting in diminished control of motor neuron firing.
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| 24. |
- Zelano, Johan, et al.
(författare)
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The synaptic protein encoded by the gene Slc10A4 suppresses epileptiform activity and regulates sensitivity to cholinergic chemoconvulsants
- 2013
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886 .- 1090-2430. ; 239, s. 73-81
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Tidskriftsartikel (refereegranskat)abstract
- The expanding number of disease-causing dysfunctions of synaptic proteins illustrates the importance of investigating newly discovered proteins involved in neuronal transmission. The gene Slc10A4 encodes a recently described carrier protein present in pre-synaptic terminals of cholinergic and monoaminergic neurons. The biological significance of this recently described transporter protein is currently unknown. We here investigated whether absence of the Slc10a4 protein has any impact on function of the cholinergic system. We first investigated the sensitivity of Slc10a4 null mice to cholinergic stimulus in vitro. In contrast to wild type mice, gamma oscillations occurred spontaneously in hippocampal slices from Slc10a4 null mice. Furthermore, moderate treatment of Slc10a4 null slices with the cholinergic agonist carbachol induced epileptiform activity. In vivo, 3-channel EEG measurements in freely behaving mice revealed that Slc10a4 null mice had frequent epileptiform spike-activity before treatment, and developed epileptic seizures, detected by EEG and accompanied by observable behavioral components, more rapidly after injection of the cholinergic agonist pilocarpine. Similar results were obtained on non-operated mice, as evaluated by behavioral seizures and post mortem c-Fos immunohistochemistry. Importantly, Slc10a4 null mice and wild type control mice were equally sensitive to the glutamatergic chemoconvulsant kainic acid, demonstrating that absence of Slc10a4 led to a selective cholinergic hypersensitivity. In summary, we report that absence of the recently discovered synaptic vesicle protein Slc10a4 results in increased sensitivity to cholinergic stimulation.
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