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- 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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- Edlund, Anna K., 1983-, et al.
(författare)
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Plasma Apolipoprotein E3 and Glucose Levels Are Associated in APOE ɛ3/ɛ4 Carriers
- 2021
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 81:1, s. 339-354
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Tidskriftsartikel (refereegranskat)abstract
- Background: Altered cerebral glucose metabolism, especially prominent in APOE ɛ4 carriers, occurs years prior to symptoms in Alzheimer’s disease (AD). We recently found an association between a higher ratio of plasma apolipoprotein E4 (apoE4) over apoE3, and cerebral glucose hypometabolism in cognitively healthy APOE ɛ3/ɛ4 subjects. Plasma apoE does not cross the blood-brain barrier, hence we speculate that apoE is linked to peripheral glucose metabolism which is known to affect glucose metabolism in the brain.Objective: Explore potential associations between levels of plasma insulin and glucose with previously acquired plasma apoE, cerebral metabolic rate of glucose (CMRgl), gray matter volume, and neuropsychological test scores.Methods: Plasma insulin and glucose levels were determined by ELISA and a glucose oxidase assay whereas apoE levels were earlier quantified by mass-spectrometry in 128 cognitively healthy APOE ɛ3/ɛ4 subjects. Twenty-five study subjects had previously undergone FDG-PET and structural MRI.Results: Lower plasma apoE3 associated with higher plasma glucose but not insulin in male subjects and subjects with a body mass index above 25. Negative correlations were found between plasma glucose and CMRgl in the left prefrontal and bilateral occipital regions. These associations may have functional implications since glucose levels in turn were negatively associated with neuropsychological test scores.Conclusion: Plasma apoE3 but not apoE4 may be involved in insulin-independent processes governing plasma glucose levels. Higher plasma glucose, which negatively affects brain glucose metabolism, was associated with lower plasma apoE levels in APOE ɛ3/ɛ4 subjects. High plasma glucose and low apoE levels may be a hazardous combination leading to an increased risk of AD.
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- Edlund, Anna, 1983-
(författare)
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Links between plasma apoE and glucose metabolism, brain insulin signaling, and synaptic integrity : Relevance to Alzheimer’s disease pathophysiology
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Human apolipoprotein E (apoE) exists as three main isoforms called apoE2, apoE3, and apoE4, of which the E4 isoform is associated with increased Alzheimer’s disease (AD) risk. Brain glucose hypometabolism, linked to synaptic dysfunction, occurs years before symptom onset in AD, especially in APOEε4-carriers. An association between a higher ratio of plasma apoE4 to apoE3 levels and cerebral glucose hypometabolism was recently discovered in cognitively healthy APOEε3/ε4 subjects. A lower plasma apoE level, regardless of isoform, is linked to increased AD risk. How the plasma apoE level affects neurodegenerative processes in the brain is poorly understood, given that apoE doesn’t cross the blood-brain barrier (BBB). The main aim of this thesis was therefore to investigate a relationship between plasma apoE and features of AD pathophysiology. We explored plasma apoE levels and dimer/monomer formation in APOEε3 and APOEε4 homozygous controls, in patients with mild cognitive impairment (MCI) and AD. In APOEε4-carriers versus non-carriers, plasma apoE levels were lower and significantly correlated with AD biomarkers. ApoE3 homodimers were less in AD patients than in controls. We next examined potential links between plasma apoE, glucose, and insulin levels in the previously examined cognitively healthy APOEε3/ε4 subjects. Lower plasma apoE3 was associated with higher glucose levels in males and subjects with body max index above 25. Plasma glucose levels were negatively correlated with the cerebral metabolic rate of glucose and neuropsychological test scores. To explore the potential effects of a hepatic APOEε4 phenotype on the brain, we compared liver humanized mice with an APOEε4/ε4 versus an APOEε2/ε3 genotype. Mice with an APOEε4/ε4 liver exhibited reduced endogenous mouse apoE in the brain, accompanied by changes in markers of synaptic integrity and insulin signaling. Plasma apoE4 levels were negatively associated with some of the assessed markers. We further explored the effects of a high-fat diet (HFD) in mice with livers humanized with the AD risk-neutral APOEε3/ε3 genotype. Endogenous mouse apoE was increased in the hippocampus following an HFD, with concomitant effects on levels of synaptic markers. In the cortex, we found altered levels of insulin signaling and synaptic markers. Together, our findings indicate that alterations in apoE levels or distribution, hepatic APOEε4 phenotype, and HFD contribute to AD-related pathological processes.Amyloidogenic processing of the amyloid precursor protein (APP) gives rise to Aβ peptides that assemble into the Aβ plaques found in AD. The binding of the adaptor protein Fe65, through its PTB2, to APP might enhance amyloidogenic APP processing. Fe65 is localized both in the cytoplasm and in the nucleus, with compartment-specific biological functions. Mechanisms affecting Fe65 subcellular localization are poorly understood. We explored the impact of the different Fe65 interaction domains WW and PTB2 and APP processing on Fe65 cellular localization. By transfecting Fe65-domain deletion constructs into neuroblastoma cell lines, we found that deleting the PTB2 domain almost abolished nuclear localization. Upon pharmacological inhibition of APP secretases, we found decreased Fe65 localization to the nucleus. To conclude, Fe65-APP interaction and APP processing may be important factors governing the Fe65 cellular localization.
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- Edlund, Jens, et al.
(författare)
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3rd party observer gaze as a continuous measure of dialogue flow
- 2012
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Ingår i: Proceedings of the 8th International Conference on Language Resources and Evaluation, LREC 2012. - Istanbul, Turkey : LREC. ; , s. 1354-1358
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Konferensbidrag (refereegranskat)abstract
- We present an attempt at using 3rd party observer gaze to get a measure of how appropriate each segment in a dialogue is for a speaker change. The method is a step away from the current dependency of speaker turns or talkspurts towards a more general view of speaker changes. We show that 3rd party observers do indeed largely look at the same thing (the speaker), and how this can be captured and utilized to provide insights into human communication. In addition, the results also suggest that there might be differences in the distribution of 3rd party observer gaze depending on how information-rich an utterance is.
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- 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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| 9. |
- 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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