The small HDL particle hypothesis of Alzheimer's disease

Martinez, Ashley E.; Weissberger, Gali H.; Kuklenyik, Zsuzsanna; He, Xianfei; Meuret, Cristiana; Parekh, Trusha; Rees, Jon C.; Parks, Bryan A.; Gardner, Michael S.; King, Samuel T.; Collier, Timothy S.; Harrington, Michael G.; Sweeney, Melanie D.; Wang, Xinhui; Zloković, Berislav V.; Nation, Daniel A.; Schneider, Lon S.; Chui, Helena C.; Barr, John R.; Han, S. Duke; Krauss, Ronald M.; Yassine, Hussein N.

doi:10.1002/alz.12649

Cited by 30 publications

(28 citation statements)

References 90 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar findings have been replicated by previous studies although an adequate explanation on these observations is yet to be fully realized [37,40,41]. Of note, Martinez et al recently showed small HDL was the only lipoprotein that could pass the BBB, which implies it plays a role in the balance and distribution of fats within the brain [42]. Potentially, HDL exerts its neuroprotective effects through the redistribution of lipids which may affect neuronal membrane composition.…”

Section: Discussionsupporting

confidence: 65%

“…Potentially, HDL exerts its neuroprotective effects through the redistribution of lipids which may affect neuronal membrane composition. This may have reverberating effects on β deposition and p-tau accumulation, and may protect neurons against oxidation and inflammation, thereby preserving vascular and synaptic function [40,42,43]. Total lipids, cholesteryl esters, cholesterol, triglycerides in VLDL and LDL subclasses, and polyunsaturated fatty acids (PUFA) were inversely associated with future risk of dementia, while free cholesterol concentration in very large VLDL was associated with an increased risk of dementia.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Plasma metabolomic profiles of dementia: a prospective study of 110,655 participants in the UK Biobank

Zhang

Wang

et al. 2022

BMC Med

View full text Add to dashboard Cite

Background Plasma metabolomic profile is disturbed in dementia patients, but previous studies have discordant conclusions. Methods Circulating metabolomic data of 110,655 people in the UK Biobank study were measured with nuclear magnetic resonance technique, and incident dementia records were obtained from national health registers. The associations between plasma metabolites and dementia were estimated using Cox proportional hazard models. The 10-fold cross-validation elastic net regression models selected metabolites that predicted incident dementia, and a 10-year prediction model for dementia was constructed by multivariable logistic regression. The predictive values of the conventional risk model, the metabolites model, and the combined model were discriminated by comparison of area under the receiver operating characteristic curves (AUCs). Net reclassification improvement (NRI) was used to estimate the change of reclassification ability when adding metabolites into the conventional prediction model. Results Amongst 110,655 participants, the mean (standard deviation) age was 56.5 (8.1) years, and 51 186 (46.3%) were male. A total of 1439 (13.0%) developed dementia during a median follow-up of 12.2 years (interquartile range: 11.5–12.9 years). A total of 38 metabolites, including lipids and lipoproteins, ketone bodies, glycolysis-related metabolites, and amino acids, were found to be significantly associated with incident dementia. Adding selected metabolites (n=24) to the conventional dementia risk prediction model significantly improved the prediction for incident dementia (AUC: 0.824 versus 0.817, p =0.042) and reclassification ability (NRI = 4.97%, P = 0.009) for identifying high risk groups. Conclusions Our analysis identified various metabolomic biomarkers which were significantly associated with incident dementia. Metabolomic profiles also provided opportunities for dementia risk reclassification. These findings may help explain the biological mechanisms underlying dementia and improve dementia prediction.

show abstract

Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Plasma metabolomic profiles of dementia: a prospective study of 110,655 participants in the UK Biobank

Zhang

Wang

et al. 2022

BMC Med

View full text Add to dashboard Cite

show abstract

“…Thus, a high concentration of intracellular cholesterol or its derivatives in astrocytes activates LXR/RXR-mediated transcription for cholesterol transport proteins to facilitate efflux [ 46 , 47 ]. In this sense, the co-expression of ApoE with ABCA1 by the LXR/RXR system reinforces the important role of ApoE lipidation in the efflux process [ 48 ]. ABCA1 may also play a critical role in removing excess cholesterol from neurons, which can either be converted into cholesterol esters and kept in the cytoplasm or converted to 24S-hydroxycholesterol (HC) by 24-hydroxylase [ 49 , 50 ], as discussed below.…”

Section: Hdl-mediated Cholesterol Trafficking In the Cnsmentioning

confidence: 87%

“…ApoA-I’s presence in the CSF derives from the blood circulating HDL [ 71 , 72 ]. The ABCA1 and ABCG1 transporters present on epithelial cells of the BBB can mediate the lipidation of peripheral apolipoproteins after their entry into the CNS [ 48 , 73 ], facilitating the formation of ApoE/ApoA-I small HDL-like particles [ 34 ]. Moreover, small HDL plasma particles can enter the brain via SR-BI-mediated uptake and transcytosis [ 34 ].…”

Section: Hdl-mediated Cholesterol Trafficking In the Cnsmentioning

confidence: 99%

HDL-like-Mediated Cell Cholesterol Trafficking in the Central Nervous System and Alzheimer’s Disease Pathogenesis

Borràs

Mercer

Sirisi

et al. 2022

IJMS

View full text Add to dashboard Cite

The main aim of this work is to review the mechanisms via which high-density lipoprotein (HDL)-mediated cholesterol trafficking through the central nervous system (CNS) occurs in the context of Alzheimer’s disease (AD). Alzheimer’s disease is characterized by the accumulation of extracellular amyloid beta (Aβ) and abnormally hyperphosphorylated intracellular tau filaments in neurons. Cholesterol metabolism has been extensively implicated in the pathogenesis of AD through biological, epidemiological, and genetic studies, with the APOE gene being the most reproducible genetic risk factor for the development of AD. This manuscript explores how HDL-mediated cholesterol is transported in the CNS, with a special emphasis on its relationship to Aβ peptide accumulation and apolipoprotein E (ApoE)-mediated cholesterol transport. Indeed, we reviewed all existing works exploring HDL-like-mediated cholesterol efflux and cholesterol uptake in the context of AD pathogenesis. Existing data seem to point in the direction of decreased cholesterol efflux and the impaired entry of cholesterol into neurons among patients with AD, which could be related to impaired Aβ clearance and tau protein accumulation. However, most of the reviewed studies have been performed in cells that are not physiologically relevant for CNS pathology, representing a major flaw in this field. The ApoE4 genotype seems to be a disruptive element in HDL-like-mediated cholesterol transport through the brain. Overall, further investigations are needed to clarify the role of cholesterol trafficking in AD pathogenesis.

show abstract

“…Although it is not yet clear whether and how peripheral HDL particles cross the blood–brain barrier, studies have found high correlations between plasma and cerebrospinal fluid concentrations of HDL-associated apoproteins that are known not to be expressed in the CNS [ 39 , 40 ]. Additionally, the peripheral overexpression of human ApoA-I improved the cognitive function, reduced neuroinflammation, and protected mice from cerebral amyloid angiopathy [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

High-Density Lipoprotein Changes in Alzheimer’s Disease Are APOE Genotype-Specific

et al. 2022

View full text Add to dashboard Cite

High-density lipoproteins (HDL) play a critical role in cholesterol homeostasis. Apolipoprotein E (APOE), particularly the E4 allele, is a significant risk factor for Alzheimer’s disease but is also a key HDL-associated protein involved in lipid transport in both the periphery and central nervous systems. The objective was to determine the influence of the APOE genotype on HDL function and size in the context of Alzheimer’s disease. HDL from 194 participants (non-demented controls, mild cognitive impairment, and Alzheimer’s disease dementia) were isolated from the plasma. The HDL cholesterol efflux capacity (CEC), lecithin-cholesterol acyltransferase (LCAT) activity, and particle diameter were measured. Neuropsychological test scores, clinical dementia rating, and magnetic resonance imaging scores were used to determine if cognition is associated with HDL function and size. HDL CEC and LCAT activity were reduced in APOE3E4 carriers compared to APOE3E3 carriers, regardless of diagnosis. In APOE3E3 carriers, CEC and LCAT activity were lower in patients. In APOE3E4 patients, the average particle size was lower. HDL LCAT activity and particle size were positively correlated with the neuropsychological scores and negatively correlated with the clinical dementia rating. We provide evidence for the first time of APOE genotype-specific alterations in HDL particles in Alzheimer’s disease and an association between HDL function, size, and cognitive function.

show abstract

The small HDL particle hypothesis of Alzheimer's disease

Cited by 30 publications

References 90 publications

Plasma metabolomic profiles of dementia: a prospective study of 110,655 participants in the UK Biobank

Plasma metabolomic profiles of dementia: a prospective study of 110,655 participants in the UK Biobank

HDL-like-Mediated Cell Cholesterol Trafficking in the Central Nervous System and Alzheimer’s Disease Pathogenesis

High-Density Lipoprotein Changes in Alzheimer’s Disease Are APOE Genotype-Specific

Contact Info

Product

Resources

About