Apolipoprotein E imbalance in the cerebrospinal fluid of Alzheimer’s disease patients

Lennol, Matthew P.; Sánchez-Domínguez, Irene; Cuchillo-Ibáñez, Inmaculada; Camporesi, Elena; Brinkmalm, Gunnar; Alcolea, Daniel; Fortea, Juan; Lleó, Alberto; Sòria, Guadalupe; Aguado, Fernando; Zetterberg, Henrik; Blennow, Kaj; Sáez‐Valero, Javier

doi:10.1186/s13195-022-01108-2

Cited by 8 publications

(6 citation statements)

References 66 publications

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“…Here, we observed greater CSF total and secondary glycosylation patterns in the MCI vs NCI group and lower CSF secondary glycosylation in AD vs MCI group, likely explained by having more APOE Ɛ4 homozygotes in the NCI group (Tables 1 and 2 ). A similar trend of reduced sialylation in AD was observed in another study [ 36 ]. While only the non-Ɛ4 carriers in the MCI group showed greater CSF glycosylation, a limitation in this analysis is posed by the presence of only three Ɛ4 allele carriers in the MCI group (Fig.…”

Section: Discussionsupporting

confidence: 88%

An association of CSF apolipoprotein E glycosylation and amyloid-beta 42 in individuals who carry the APOE4 allele

Meuret

Smadi

et al. 2023

Alz Res Therapy

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Carrying the apolipoprotein E (ApoE) Ɛ4 allele is associated with an increased risk of cerebral amyloidosis and late-onset Alzheimer’s disease, but the degree to which apoE glycosylation affects its development is not clear. In a previous pilot study, we identified distinct total and secondary isoform-specific cerebral spinal fluid (CSF) apoE glycosylation profiles, with the E4 isoform having the lowest glycosylation percentage (E2 > E3 > E4). In this work, we extend the analysis to a larger cohort of individuals (n = 106), utilizing matched plasma and CSF samples with clinical measures of AD biomarkers. The results confirm the isoform-specific glycosylation of apoE in CSF, resulting from secondary CSF apoE glycosylation patterns. CSF apoE glycosylation percentages positively correlated with CSF Aβ42 levels (r = 0.53, p < 0.0001). These correlations were not observed for plasma apoE glycosylation. CSF total and secondary apoE glycosylation percentages also correlated with the concentration of CSF small high-density lipoprotein particles (s-HDL-P), which we have previously shown to be correlated with CSF Aβ42 levels and measures of cognitive function. Desialylation of apoE purified from CSF showed reduced Aβ42 degradation in microglia with E4 > E3 and increased binding affinity to heparin. These results indicate that apoE glycosylation has a new and important role in influencing brain Aβ metabolism and can be a potential target of treatment.

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Section: Discussionsupporting

confidence: 88%

An association of CSF apolipoprotein E glycosylation and amyloid-beta 42 in individuals who carry the APOE4 allele

Meuret

Smadi

et al. 2023

Alz Res Therapy

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“…Having previously shown that plasma apoE disulfide dimers are of relevance to AD [ 16 ], we here aimed to also assess the existence of plasma apoE in monomers and dimers and to investigate whether the apoE monomer/dimer profile is influenced by APOE ε4 heterozygosity, race/ethnicity, and/or AD. The presence of cysteine residue(s) in the apoE3 and apoE2 isoforms allows these isoforms to form disulfide dimeric structures which previously have been documented in the plasma, CSF, and the cortex and hippocampus [ 16 , 39 – 43 ]. Using SDS-PAGE under non-reducing conditions followed by western blot analysis, we detected two bands of approximately 43 kDa and 95 kDa corresponding to apoE3-apoA-II heterodimers and apoE3-apoE3 homodimers in all plasma samples from subjects with the APOE ε3/ε3 and APOE ε3/ε4 genotypes (Additional file 1 : Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We also observed that the ratio of apoE monomers/dimers was unrelated to clinical diagnosis and CSF AD biomarkers. Interestingly, previously, it was shown that CSF and brain apoE dimers did not differ between AD patients and cognitively healthy controls [ 41 , 43 , 72 ]. In our earlier work, we however observed that plasma apoE3 homodimers were linked to worse cognition and higher tau/Aβ 42 ratios in APOE ε3/ε3 Norwegian individuals [ 16 ], suggesting a positive association between plasma apoE3 homodimers and AD pathology.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2023

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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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“…We next measured cholesterol esterification in the CSF of AD patients and found that CER was strongly reduced compared to controls, and the unesterified/total cholesterol was strongly increased in the CSF of AD patients, where around 50% of cholesterol is not esterified. As in the plasma, most of the CEs in the CSF should be LCAT-derived, thus suggesting a dysregulation of the LCAT system in AD CSF, which could be partly explained by the presence of unfunctional apoE in CSF of AD patients [ 36 ]. The lower content of CEs in AD CSF could also derive from the accumulation of CEs in the brain, and indeed excess CEs have been shown in brain vulnerable regions of AD patients [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Plasma and cerebrospinal fluid cholesterol esterification is hampered in Alzheimer’s disease

Turri¹,

Conti²,

Pavanello³

et al. 2023

Alz Res Therapy

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Objective The purpose of this study was to evaluate cholesterol esterification and HDL subclasses in plasma and cerebrospinal fluid (CSF) of Alzheimer’s disease (AD) patients. Methods The study enrolled 70 AD patients and 74 cognitively normal controls comparable for age and sex. Lipoprotein profile, cholesterol esterification, and cholesterol efflux capacity (CEC) were evaluated in plasma and CSF. Results AD patients have normal plasma lipids but significantly reduced unesterified cholesterol and unesterified/total cholesterol ratio. Lecithin:cholesterol acyltransferase (LCAT) activity and cholesterol esterification rate (CER), two measures of the efficiency of the esterification process, were reduced by 29% and 16%, respectively, in the plasma of AD patients. Plasma HDL subclass distribution in AD patients was comparable to that of controls but the content of small discoidal preβ-HDL particles was significantly reduced. In agreement with the reduced preβ-HDL particles, cholesterol efflux capacity mediated by the transporters ABCA1 and ABCG1 was reduced in AD patients’ plasma. The CSF unesterified to total cholesterol ratio was increased in AD patients, and CSF CER and CEC from astrocytes were significantly reduced in AD patients. In the AD group, a significant positive correlation was observed between plasma unesterified cholesterol and unesterified/total cholesterol ratio with Aβ1-42 CSF content. Conclusion Taken together our data indicate that cholesterol esterification is hampered in plasma and CSF of AD patients and that plasma cholesterol esterification biomarkers (unesterified cholesterol and unesterified/total cholesterol ratio) are significantly associated to disease biomarkers (i.e., CSF Aβ1-42).

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Apolipoprotein E imbalance in the cerebrospinal fluid of Alzheimer’s disease patients

Cited by 8 publications

References 66 publications

An association of CSF apolipoprotein E glycosylation and amyloid-beta 42 in individuals who carry the APOE4 allele

An association of CSF apolipoprotein E glycosylation and amyloid-beta 42 in individuals who carry the APOE4 allele

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

Plasma and cerebrospinal fluid cholesterol esterification is hampered in Alzheimer’s disease

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