Association of Apolipoprotein E in Lipoprotein Subspecies With Risk of Dementia

Koch, Manja; DeKosky, Steven T.; Goodman, Matthew; Sun, Jiehuan; Furtado, Jeremy; Fitzpatrick, Annette L.; Mackey, Rachel H.; Cai, Tianxi; López, Oscar L.; Kuller, Lewis H.; Mukamal, Kenneth J.; Jensen, Majken K.

doi:10.1001/jamanetworkopen.2020.9250

Cited by 24 publications

(20 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, HDL particles enriched in apoE reduce Aβ deposition in the cerebrovascular wall independently of SR-BI while requiring HDL crossing the endothelial barrier [ 181 ]. These results are in line with recent epidemiological data showing that HDL containing apoE but not apoCIII is inversely associated with AD risk [ 182 ]. Together these results open new questions whether HDL subpopulations differ by their interactions with endothelial cells of the BBB.…”

Section: Hdl and Blood–brain Barrier Function In Stroke And Neurodegenerative Diseasessupporting

confidence: 92%

The Endothelium Is Both a Target and a Barrier of HDL’s Protective Functions

Robert

Osto

Eckardstein

2021

Cells

View full text Add to dashboard Cite

The vascular endothelium serves as a barrier between the intravascular and extravascular compartments. High-density lipoproteins (HDL) have two kinds of interactions with this barrier. First, bloodborne HDL must pass the endothelium to access extravascular tissues, for example the arterial wall or the brain, to mediate cholesterol efflux from macrophages and other cells or exert other functions. To complete reverse cholesterol transport, HDL must even pass the endothelium a second time to re-enter circulation via the lymphatics. Transendothelial HDL transport is a regulated process involving scavenger receptor SR-BI, endothelial lipase, and ATP binding cassette transporters A1 and G1. Second, HDL helps to maintain the integrity of the endothelial barrier by (i) promoting junction closure as well as (ii) repair by stimulating the proliferation and migration of endothelial cells and their progenitor cells, and by preventing (iii) loss of glycocalix, (iv) apoptosis, as well as (v) transmigration of inflammatory cells. Additional vasoprotective functions of HDL include (vi) the induction of nitric oxide (NO) production and (vii) the inhibition of reactive oxygen species (ROS) production. These vasoprotective functions are exerted by the interactions of HDL particles with SR-BI as well as specific agonists carried by HDL, notably sphingosine-1-phophate (S1P), with their specific cellular counterparts, e.g., S1P receptors. Various diseases modify the protein and lipid composition and thereby the endothelial functionality of HDL. Thorough understanding of the structure–function relationships underlying the multiple interactions of HDL with endothelial cells is expected to elucidate new targets and strategies for the treatment or prevention of various diseases.

show abstract

Section: Hdl and Blood–brain Barrier Function In Stroke And Neurodegenerative Diseasessupporting

confidence: 92%

The Endothelium Is Both a Target and a Barrier of HDL’s Protective Functions

Robert

Osto

Eckardstein

2021

Cells

View full text Add to dashboard Cite

show abstract

“…Previous work has linked higher APOC3 levels in HDL to an increased risk of coronary heart disease and diabetes, both of which are known risk factors for dementia 25,26 . Higher APOE levels in HDL lacking APOC3 in an elderly population were related to better cognitive function and a lower risk of AD dementia 27 . In this context, it is of note that the lipid-binding affinity of APOEε4 is higher than those of APOEε2 and APOEε3 22,23 , a property that likely accounts for the tendency of APOEε4 to associate with VLDL, while the ε2 and ε3 alleles related to HDL.…”

Section: Discussionmentioning

confidence: 93%

Impact of APOE ε3 and ε4 genotypes on plasma proteome signatures in Alzheimer’s disease

Kaur

Poljak

Masters

et al. 2022

Preprint

View full text Add to dashboard Cite

The e4 allele of the apolipoprotein E (APOE) gene is a high-risk factor for Alzheimer's disease (AD). However, approximately 25% to 40% of patients with AD do not carry the APOE e4 allele, and the pathophysiological mechanisms underlying AD are less evident in these individuals. The main objective of this study was to understand better the changes in plasma that may contribute to disease pathogenesis in AD and how APOE e3 and APOE e4 contribute to biomarker profiles in AD. We conducted an in-depth plasma proteomics analysis using intensive depletion of high-abundant plasma proteins using the Agilent multiple affinity removal liquid chromatography (LC) column- Human 14 (Hu14) followed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS PAGE) technique. In this study, we identified a high number of protein expression alterations in plasma which were found uniquely in APOE e3 and APOE e4 carriers. These differentially expressed proteins (DEPs) were associated with several molecular functions, including complement cascade, glycolysis, metabolism, plasma lipoprotein assembly, remodelling, and clearance. In addition to unique changes in both APOE genotypes, many proteins were also dysregulated in the presence of both APOE e3 and APOE e4 genotypes depicting the involvement of these proteins in the pathogenesis of AD regardless of the APOE genotypes. We also compared the plasma proteomes of e4 and e3 carriers in normal controls, which provided insight into factors that may provide protection from progression to AD despite the presence of the e4 allele. Furthermore, our findings also identified some proteins previously discovered in AD CSF and brain proteomics signatures that could provide clinically meaningful information.

show abstract

“…Although it remains controversial whether and how peripheral APOE may contribute to AD pathogenesis [ 46 , 342 ], evidence suggests that low plasma APOE levels are associated with increased AD and dementia risk, independent of APOE genotype [ 343 , 344 ]. Moreover, higher levels of APOE in APOC3-free HDL particles in the plasma have been associated with better cognitive performance and reduced risk of dementia in humans [ 345 ]. Since APOE*ε2 carriers have higher levels of plasma APOE [ 48 – 51 ] and HDL [ 92 , 93 ], whole plasma or plasma APOE-containing lipoprotein particles from APOE*ε2 carriers may hold promise as a therapeutic strategy for AD.…”

Section: Main Textmentioning

confidence: 99%

APOE2: protective mechanism and therapeutic implications for Alzheimer’s disease

Shue

Zhao

et al. 2020

Mol Neurodegeneration

152

119

View full text Add to dashboard Cite

Investigations of apolipoprotein E (APOE) gene, the major genetic risk modifier for Alzheimer’s disease (AD), have yielded significant insights into the pathogenic mechanism. Among the three common coding variants, APOE*ε4 increases, whereas APOE*ε2 decreases the risk of late-onset AD compared with APOE*ε3. Despite increased understanding of the detrimental effect of APOE*ε4, it remains unclear how APOE*ε2 confers protection against AD. Accumulating evidence suggests that APOE*ε2 protects against AD through both amyloid-β (Aβ)-dependent and independent mechanisms. In addition, APOE*ε2 has been identified as a longevity gene, suggesting a systemic effect of APOE*ε2 on the aging process. However, APOE*ε2 is not entirely benign; APOE*ε2 carriers exhibit increased risk of certain cerebrovascular diseases and neurological disorders. Here, we review evidence from both human and animal studies demonstrating the protective effect of APOE*ε2 against AD and propose a working model depicting potential underlying mechanisms. Finally, we discuss potential therapeutic strategies designed to leverage the protective effect of APOE2 to treat AD.

show abstract

Association of Apolipoprotein E in Lipoprotein Subspecies With Risk of Dementia

Cited by 24 publications

References 42 publications

The Endothelium Is Both a Target and a Barrier of HDL’s Protective Functions

The Endothelium Is Both a Target and a Barrier of HDL’s Protective Functions

Impact of APOE ε3 and ε4 genotypes on plasma proteome signatures in Alzheimer’s disease

APOE2: protective mechanism and therapeutic implications for Alzheimer’s disease

Contact Info

Product

Resources

About