| 1. |
- 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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| 2. |
- Giannisis, Andreas, et al.
(författare)
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Plasma apolipoprotein E levels, isoform composition and dimer profile in relation to plasma lipids in racially diverse patients with Alzheimer’s disease and mild cognitive impairment
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: The APOEε4-promoted risk of Alzheimer’s disease (AD) is lower in Black/African-Americans (B/AA), compared to Non-Hispanic whites (NHWs). Previous studies reported lower plasma apolipoprotein E (apoE) levels in NHW APOEε4-carriers compared to non-carriers, and low plasma apoE levels were directly associated with an increased risk of AD and all dementia. We further showed that APOEε3/ε3 AD patients exhibited reduced plasma apoE dimers compared to corresponding control subjects. Whether plasma apoE levels and apoE dimer formation differ due to race, and therefore may help explain AD-risk racial disparity, remains to be elucidated. Methods: Using mass spectrometry, we determined total plasma apoE and apoE isoform levels in a cohort of B/AAs (n=58) and NHWs (n=67) including subjects with normal cognition (B/AA: n=25, NHW: n=28), mild cognitive impairment (MCI) (B/AA: n=24, NHW: n=24), or AD dementia (B/AA: n=9, NHW: n=15). Additionally, we used non-reducing western blot analysis to assess the distribution of plasma apoE into monomers/disulfide-linked dimers. Plasma total apoE, apoE isoform levels, and %apoE monomers/dimers were assessed for correlations with cognition, cerebrospinal fluid (CSF) AD biomarkers, sTREM2, Neurofilament Light protein (NfL) and plasma lipids. Results: Plasma apoE was predominantly monomeric in both racial groups and the monomer/dimer distribution was not affected by disease status, or correlated with CSF AD biomarkers, but associated with plasma lipids. Plasma total apoE levels were not related to disease status and only in the NHW subjects we observed lower plasma apoE levels in the APOEε4/ε4-carriers. Total plasma apoE levels were 13% higher in B/AA compared to NHW APOEε4/ε4 subjects and associated with plasma high-density lipoproteins (HDL) in NHW subjects, but with low-density lipoprotein levels (LDL) in the B/AA subjects. Higher plasma apoE4 levels, exclusively in APOEε3/ε4 B/AA subjects, were linked to higher plasma total cholesterol and LDL levels. In the controls, NHWs and B/AAs exhibited opposite associations between plasma apoE and CSF t-tau. Conclusions: The previously reported lower APOEε4-promoted risk of AD in B/AA subjects may be associated with differences in plasma apoE levels and lipoprotein association. Whether race-dependent differences in plasma apoE levels result from altered APOEε4 expression or turnover, needs further elucidation.
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| 3. |
- Giannisis, Andreas, 1993-, et al.
(författare)
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Plasma apolipoprotein E levels, isoform composition, and dimer profile in relation to plasma lipids in racially diverse patients with Alzheimer’s disease and mild cognitive impairment
- 2023
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Ingår i: Alzheimer's Research & Therapy. - : Springer Nature. - 1758-9193. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Background The APOEε4-promoted risk of Alzheimer’s disease (AD) is lower in Black/African-Americans (B/AAs), compared to non-Hispanic whites (NHWs). Previous studies reported lower plasma apolipoprotein E (apoE) levels in NHW APOEε4-carriers compared to non-carriers, and low plasma apoE levels were directly associated with an increased risk of AD and all dementia. We further showed that APOEε3/ε3 AD patients exhibited reduced plasma apoE dimers compared to corresponding control subjects. Whether plasma apoE levels and apoE dimer formation differ between races/ethnicities and therefore may help explain AD risk racial disparity remains to be elucidated.Methods Using mass spectrometry, we determined total plasma apoE and apoE isoform levels in a cohort of B/AAs (n = 58) and NHWs (n = 67) including subjects with normal cognition (B/AA: n = 25, NHW: n = 28), mild cognitive impairment (MCI) (B/AA: n = 24, NHW: n = 24), or AD dementia (B/AA: n = 9, NHW: n = 15). Additionally, we used non-reducing western blot analysis to assess the distribution of plasma apoE into monomers/disulfide-linked dimers. Plasma total apoE, apoE isoform levels, and % apoE monomers/dimers were assessed for correlations with cognition, cerebrospinal fluid (CSF) AD biomarkers, sTREM2, neurofilament light protein (NfL), and plasma lipids.Results Plasma apoE was predominantly monomeric in both racial groups and the monomer/dimer distribution was not affected by disease status, or correlated with CSF AD biomarkers, but associated with plasma lipids. Plasma total apoE levels were not related to disease status and only in the NHW subjects we observed lower plasma apoE levels in the APOEε4/ε4-carriers. Total plasma apoE levels were 13% higher in B/AA compared to NHW APOEε4/ε4 subjects and associated with plasma high-density lipoprotein (HDL) in NHW subjects but with low-density lipoprotein levels (LDL) in the B/AA subjects. Higher plasma apoE4 levels, exclusively in APOEε3/ε4 B/AA subjects, were linked to higher plasma total cholesterol and LDL levels. In the controls, NHWs and B/AAs exhibited opposite associations between plasma apoE and CSF t-tau.Conclusions The previously reported lower APOEε4-promoted risk of AD in B/AA subjects may be associated with differences in plasma apoE levels and lipoprotein association. Whether differences in plasma apoE levels between races/ethnicities result from altered APOEε4 expression or turnover, needs further elucidation.
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| 4. |
- Vaivade, Aina, et al.
(författare)
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Autologous hematopoietic stem cell transplantation significantly alters circulating ceramides in peripheral blood of relapsing-remitting multiple sclerosis patients
- 2023
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Ingår i: Lipids in Health and Disease. - : BioMed Central (BMC). - 1476-511X. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The common inflammatory disease multiple sclerosis (MS) is a disease of the central nervous system. For more than 25 years autologous hematopoietic stem cell transplantation (AHSCT) has been used to treat MS. It has been shown to be highly effective in suppressing inflammatory activity in relapsing-remitting MS (RRMS) patients. This treatment is thought to lead to an immune system reset, inducing a new, more tolerant system; however, the precise mechanism behind the treatment effect in MS patients is unknown. In this study, the effect of AHSCT on the metabolome and lipidome in peripheral blood from RRMS patients was investigated.Methods: Peripheral blood samples were collected from 16 patients with RRMS at ten-time points over the five months course of AHSCT and 16 MS patients not treated with AHSCT. Metabolomics and lipidomics analysis were performed using liquid-chromatography high-resolution mass spectrometry. Mixed linear models, differential expression analysis, and cluster analysis were used to identify differentially expressed features and groups of features that could be of interest. Finally, in-house and in-silico libraries were used for feature identification, and enrichment analysis was performed.Results: Differential expression analysis found 657 features in the lipidomics dataset and 34 in the metabolomics dataset to be differentially expressed throughout AHSCT. The administration of cyclophosphamide during mobilization and conditioning was associated with decreased concentrations in glycerophosphoinositol species. Thymoglobuline administration was associated with an increase in ceramide and glycerophosphoethanolamine species. After the conditioning regimen, a decrease in glycerosphingoidlipids concentration was observed, and following hematopoietic stem cell reinfusion glycerophosphocholine concentrations decreased for a short period of time. Ceramide concentrations were strongly associated with leukocyte levels during the procedure. The ceramides Cer(d19:1/14:0) and Cer(d20:1/12:0) were found to be increased (P < .05) in concentration at the three-month follow-up compared to baseline. C16 ceramide, Cer(D18:2/16:0), and CerPE(d16:2(4E,6E)/22:0) were found to be significantly increased in concentration after AHSCT compared to prior to treatment as well as compared to newly diagnosed RRMS patients.Conclusion: AHSCT had a larger impact on the lipids in peripheral blood compared to metabolites. The variation in lipid concentration reflects the transient changes in the peripheral blood milieu during the treatment, rather than the changes in the immune system that are assumed to be the cause of clinical improvement within RRMS patients treated with AHSCT. Ceramide concentrations were affected by AHSCT and associated with leukocyte counts and were altered three months after treatment, suggesting a long-lasting effect.
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| 5. |
- Ye, Shaojing, et al.
(författare)
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Lumbosacral spinal proteomic changes during PAR4-induced persistent bladder pain
- 2024
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Ingår i: Neuroscience Letters. - : Elsevier. - 0304-3940 .- 1872-7972. ; 818
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Tidskriftsartikel (refereegranskat)abstract
- Repeated intravesical activation of protease-activated receptor-4 (PAR4) in mice results in persistent bladder hyperalgesia (BHA). We investigated spinal proteomic changes associated with persistent BHA. Persistent BHA was induced in female mice by repeated (3x; days 0,2,4; n = 9) intravesical instillation of PAR4 activating peptide (PAR4-AP) while scrambled peptide served as the control (no pain; n = 9) group. The threshold to lower abdominal von Frey stimulation was recorded prior to and during treatment. On day 7, L6-S1 spinal segments were excised and examined for proteomic changes using LC-MS/MS. In-depth, unbiased proteomic tandem-mass tag (TMT) analysis identified and relatively quantified 6739 proteins. We identified significant changes with 29 decreasing and 51 increasing proteins in the persistent BHA group and they were associated with neuroprotection, redox modulation, mitochondrial factors, and neuronal-related proteins. In an additional experiment, decreases in protein levels were confirmed by immunohistochemistry for metallothionein 1/2. Our results show that persistent bladder pain is associated with central (spinal) protein changes. Previous work showed that PAR4induced bladder pain is mediated, at least in part by spinal MIF. Further functional studies of these top changing proteins may lead to the discovery of novel potential therapeutic targets at the spinal level to modulate persistent bladder pain. Future studies will examine the effect of spinal MIF antagonism on PAR4-induced spinal proteomics associated with persistent bladder pain.
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