| 1. |
- Kloske, C. M., et al.
(författare)
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APOE and immunity: Research highlights
- 2023
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:6, s. 2677-2696
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Forskningsöversikt (refereegranskat)abstract
- INTRODUCTIONAt the Alzheimer's Association's APOE and Immunity virtual conference, held in October 2021, leading neuroscience experts shared recent research advances on and inspiring insights into the various roles that both the apolipoprotein E gene (APOE) and facets of immunity play in neurodegenerative diseases, including Alzheimer's disease and other dementias. METHODSThe meeting brought together more than 1200 registered attendees from 62 different countries, representing the realms of academia and industry. RESULTSDuring the 4-day meeting, presenters illuminated aspects of the cross-talk between APOE and immunity, with a focus on the roles of microglia, triggering receptor expressed on myeloid cells 2 (TREM2), and components of inflammation (e.g., tumor necrosis factor alpha [TNF alpha]). DISCUSSIONThis manuscript emphasizes the importance of diversity in current and future research and presents an integrated view of innate immune functions in Alzheimer's disease as well as related promising directions in drug development.
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| 2. |
- 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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| 3. |
- 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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| 4. |
- 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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| 5. |
- 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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| 6. |
- Fernández-Calle, Rosalía, et al.
(författare)
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APOE in the bullseye of neurodegenerative diseases : impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases
- 2022
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Ingår i: Molecular Neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 17:1
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Forskningsöversikt (refereegranskat)abstract
- ApoE is the major lipid and cholesterol carrier in the CNS. There are three major human polymorphisms, apoE2, apoE3, and apoE4, and the genetic expression of APOE4 is one of the most influential risk factors for the development of late-onset Alzheimer's disease (AD). Neuroinflammation has become the third hallmark of AD, together with Amyloid-β plaques and neurofibrillary tangles of hyperphosphorylated aggregated tau protein. This review aims to broadly and extensively describe the differential aspects concerning apoE. Starting from the evolution of apoE to how APOE's single-nucleotide polymorphisms affect its structure, function, and involvement during health and disease. This review reflects on how APOE's polymorphisms impact critical aspects of AD pathology, such as the neuroinflammatory response, particularly the effect of APOE on astrocytic and microglial function and microglial dynamics, synaptic function, amyloid-β load, tau pathology, autophagy, and cell-cell communication. We discuss influential factors affecting AD pathology combined with the APOE genotype, such as sex, age, diet, physical exercise, current therapies and clinical trials in the AD field. The impact of the APOE genotype in other neurodegenerative diseases characterized by overt inflammation, e.g., alpha- synucleinopathies and Parkinson's disease, traumatic brain injury, stroke, amyotrophic lateral sclerosis, and multiple sclerosis, is also addressed. Therefore, this review gathers the most relevant findings related to the APOE genotype up to date and its implications on AD and CNS pathologies to provide a deeper understanding of the knowledge in the APOE field.
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| 7. |
- 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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| 8. |
- 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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| 9. |
- Giannisis, Andreas, 1993-
(författare)
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Peripheral apolipoprotein E and its emerging role in neurodegenerative disease
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The human apolipoprotein E gene (APOE) is polymorphic and coding for three common alleles; ε2, ε3, and ε4. Carriers of the ε4 allele are at a higher risk of developing sporadic late-onset Alzheimer’s Disease (AD). This association appears to be influenced by inherited traits, race, and sex. The connection between APOE genotype and AD-related pathological processes has been studied excessively, however, less attention has been devoted to the apolipoprotein E (apoE) protein levels per se, most possibly due to the inconsistent results presented in studies assessing potential links between cerebrospinal fluid (CSF) apoE levels and AD, and because systemic apoE cannot cross the blood-brain barrier (BBB). Nevertheless, low plasma apoE levels were found to enhance AD and dementia risk, with the APOE ε4 genotype influencing this risk by promoting a reduction of the plasma apoE levels in some populations. In this thesis, we speculate that peripheral apoE-dependent mechanisms are linked to neurodegeneration. To address this hypothesis, we performed a set of clinical and experimental studies. In the first three studies, we aimed to determine whether hepatic APOE ε4 genotype, plasma apoE levels, and diet are linked to brain function and cognition by utilizing a mouse model with humanized-livers that are characterized by the presence of human apoE only in the plasma. A comparison between the brains of APOE ε4/ε4 and APOE ε2/ε3 humanized-liver mice revealed altered endogenous murine apoe levels as well as altered levels of synaptic, neuroinflammatory, and insulin signaling-related markers in the cortex and hippocampus. Higher plasma apoE4 levels were also linked to these associations, mainly in the hippocampus of the humanized APOE ε4/ε4 liver mice. A similar, though less pronounced, effect was observed in the brains of APOE ε3/ε3 humanized-liver mice that were fed a high-fat, versus a normal diet. Utilizing the plasma from APOE ε3/ε3 humanized-liver mice, we further observed that the distribution of apoE3 in plasma lipoparticles differed between sexes. In addition, higher total plasma apoE3 levels were beneficial to the activity levels but appeared to have a negative impact on cognition in these mice. In the remaining studies, we aimed to determine how plasma apoE levels, apoE isoform distribution, and the formation of monomers and disulfide-linked homodimers and heterodimers with apolipoprotein A-II (apoA-II) are influenced by APOE genotype and AD. For that purpose, we studied two cohorts of Norwegian, Black/African-American (B/AA), and non-Hispanic white (NHW) cognitively healthy subjects and patients with AD or mild cognitive impairment (MCI). Only in Norwegian individuals, we observed lower levels of plasma apoE due to AD and APOE ε4 genotype. In addition, in these subjects, the apoE monomer/dimer profile seemed to be influenced by AD status. In the cohort of B/AAs and NHWs, these associations were absent. In both cohorts, we observed associations between plasma apoE levels and CSF AD biomarker levels. Lastly, B/AA subjects presented the highest plasma apoE levels with APOE ε4/ε4-carrying subjects exhibiting significantly higher plasma apoE levels than NHW APOE ε4/ε4 subjects.Overall, our studies suggest that hepatic APOE genotype and plasma apoE levels are associated with AD-related neuropathological changes which seem to be influenced by other factors like race and diet. Whether this influence is due to differences in apoE levels or apoE function (i.e. different distribution between lipoparticles) remains to be investigated in future studies.
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| 10. |
- 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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