The Role of HDL and HDL Mimetic Peptides as Potential Therapeutics for Alzheimer’s Disease

Chernick, Dustin; Zhong, Rui; L, Li

doi:10.3390/biom10091276

Cited by 19 publications

(14 citation statements)

References 236 publications

(309 reference statements)

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“…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%

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

Zhang

Wang

et al. 2022

BMC Med

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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.

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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

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“…Due to the role of apoE in Alzheimer’s disease development and other neurologic diseases, apoE mimetic peptides have also been tested in various neurologic disease animal models and have yielded promising results [ 111 ]. One example of an apoE mimetic peptide designed for Alzheimer’s disease is CN-105 (Cerenova, LLC) ( Table 4 ).…”

Section: Apoementioning

confidence: 99%

“…It was tested in 48 subjects in a phase 1 trial and shown to be safe [ 104 ]. Several other apoE-based peptides for neurologic diseases are actively being developed and have recently been reviewed [ 111 ].…”

Section: Apoementioning

confidence: 99%

Apolipoprotein Mimetic Peptides: Potential New Therapies for Cardiovascular Diseases

Wolska

Reimund

Sviridov

et al. 2021

Cells

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Since the seminal breakthrough of treating diabetic patients with insulin in the 1920s, there has been great interest in developing other proteins and their peptide mimetics as therapies for a wide variety of other medical disorders. Currently, there are at least 60 different peptides that have been approved for human use and over 150 peptides that are in various stages of clinical development. Peptides mimetic of the major proteins on lipoproteins, namely apolipoproteins, have also been developed first as tools for understanding apolipoprotein structure and more recently as potential therapeutics. In this review, we discuss the biochemistry, peptide mimetics design and clinical trials for peptides based on apoA-I, apoE and apoC-II. We primarily focus on applications of peptide mimetics related to cardiovascular diseases. We conclude with a discussion on the limitations of peptides as therapeutic agents and the challenges that need to be overcome before apolipoprotein mimetic peptides can be developed into new drugs.

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“…apoA-I-rHDL containing elaidic acid showed impaired HDL functionality via the displacement of apoA-I from the rHDL [ 32 ]. Several atherogenic changes in HDL by carbohydrate and trans fat HDL show that good-quality HDL reduces the risk of AD via the natural clearance of Aβ [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Structural and Functional Impairments of Reconstituted High-Density Lipoprotein by Incorporation of Recombinant β-Amyloid42

Cho

2021

Molecules

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Beta (β)-amyloid (Aβ) is a causative protein of Alzheimer’s disease (AD). In the pathogenesis of AD, the apolipoprotein (apo) A-I and high-density lipoprotein (HDL) metabolism is essential for the clearance of Aβ. In this study, recombinant Aβ42 was expressed and purified via the pET-30a expression vector and E.coli production system to elucidate the physiological effects of Aβ on HDL metabolism. The recombinant human Aβ protein (51 aa) was purified to at least 95% purity and characterized in either the lipid-free and lipid-bound states with apoA-I. Aβ was incorporated into the reconstituted HDL (rHDL) (molar ratio 95:5:1, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC):cholesterol:apoA-I) with various apoA-I:Aβ ratios from 1:0 to 1:0.5, 1:1 and 1:2. With an increasing molar ratio of Aβ, the α-helicity of apoA-I was decreased from 62% to 36% with a red shift of the Trp wavelength maximum fluorescence from 337 to 340 nm in apoA-I. The glycation reaction of apoA-I was accelerated further by the addition of Aβ. The treatment of fructose and Aβ caused more multimerization of apoA-I in the lipid-free state and in HDL. The phospholipid-binding ability of apoA-I was impaired severely by the addition of Aβ in a dose-dependent manner. The phagocytosis of LDL into macrophages was accelerated more by the presence of Aβ with the production of more oxidized species. Aβ severely impaired tissue regeneration, and a microinjection of Aβ enhanced embryotoxicity. In conclusion, the beneficial functions of apoA-I and HDL were severely impaired by the addition of Aβ via its detrimental effect on secondary structure. The impairment of HDL functionality occurred more synergistically by means of the co-addition of fructose and Aβ.

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The Role of HDL and HDL Mimetic Peptides as Potential Therapeutics for Alzheimer’s Disease

Cited by 19 publications

References 236 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

Apolipoprotein Mimetic Peptides: Potential New Therapies for Cardiovascular Diseases

Structural and Functional Impairments of Reconstituted High-Density Lipoprotein by Incorporation of Recombinant β-Amyloid42

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