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

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.

[1]  In-Chul Lee,et al.  Native High-Density Lipoproteins (HDL) with Higher Paraoxonase Exerts a Potent Antiviral Effect against SARS-CoV-2 (COVID-19), While Glycated HDL Lost the Antiviral Activity , 2021, Antioxidants.

[2]  Ling Li,et al.  The Role of HDL and HDL Mimetic Peptides as Potential Therapeutics for Alzheimer’s Disease , 2020, Biomolecules.

[3]  S. Kanba,et al.  Serum elaidic acid concentration and risk of dementia , 2019, Neurology.

[4]  A. Sahebkar,et al.  Emerging roles for high‐density lipoproteins in neurodegenerative disorders , 2019, BioFactors.

[5]  V. Lowe,et al.  Apolipoprotein A-I Crosses the Blood-Brain Barrier through Clathrin-Independent and Cholesterol-Mediated Endocytosis , 2019, The Journal of Pharmacology and Experimental Therapeutics.

[6]  K. Cho High-Density Lipoproteins as Biomarkers and Therapeutic Tools: Volume 2. Improvement and Enhancement of HDL and Clinical Applications , 2019 .

[7]  M. Sarzynski,et al.  Effects of exercise on HDL functionality , 2019, Current opinion in lipidology.

[8]  M. Mimura,et al.  The association between midlife serum high-density lipoprotein and mild cognitive impairment and dementia after 19 years of follow-up , 2019, Translational Psychiatry.

[9]  C. E. Kosmas,et al.  High-density lipoprotein (HDL) functionality and its relevance to atherosclerotic cardiovascular disease , 2018, Drugs in context.

[10]  Sunhee Choi,et al.  Glycation of Lys-16 and Arg-5 in amyloid-β and the presence of Cu2+ play a major role in the oxidative stress mechanism of Alzheimer’s disease , 2017, JBIC Journal of Biological Inorganic Chemistry.

[11]  M. V. van Boxtel,et al.  Coronary heart disease and risk for cognitive impairment or dementia: Systematic review and meta-analysis , 2017, Alzheimer's & Dementia.

[12]  Wai Hang Cheng,et al.  Reconstituted high-density lipoproteins acutely reduce soluble brain Aβ levels in symptomatic APP/PS1 mice. , 2016, Biochimica et biophysica acta.

[13]  N. Ferlazzo,et al.  Citrus bergamia Juice Extract Attenuates β-Amyloid-Induced Pro-Inflammatory Activation of THP-1 Cells Through MAPK and AP-1 Pathways , 2016, Scientific Reports.

[14]  C. Wellington,et al.  HDL and cholesterol handling in the brain. , 2014, Cardiovascular research.

[15]  Kyung-Hyun Cho,et al.  Elaidic acid (EA) generates dysfunctional high-density lipoproteins and consumption of EA exacerbates hyperlipidemia and fatty liver change in zebrafish. , 2014, Molecular nutrition & food research.

[16]  S. Lerakis,et al.  High-Density Lipoprotein Functionality in Coronary Artery Disease , 2014, The American journal of the medical sciences.

[17]  S. Lovestone,et al.  Advanced glycation end products, dementia, and diabetes , 2014, Proceedings of the National Academy of Sciences.

[18]  W. Song,et al.  Molecular links between Alzheimer’s disease and diabetes mellitus , 2013, Neuroscience.

[19]  A. Hakim,et al.  Heart disease as a risk factor for dementia , 2013, Clinical epidemiology.

[20]  S. Hama,et al.  HDL functionality , 2012, Current opinion in lipidology.

[21]  Yining Huang,et al.  Nonenzymatic glycation of high‐density lipoprotein impairs its anti‐inflammatory effects in innate immunity , 2012, Diabetes/metabolism research and reviews.

[22]  V. Demarin,et al.  Low high-density lipoprotein cholesterol as the possible risk factor for stroke. , 2010, Acta clinica Croatica.

[23]  Dong-gu Shin,et al.  Senescence-related truncation and multimerization of apolipoprotein A-I in high-density lipoprotein with an elevated level of advanced glycated end products and cholesteryl ester transfer activity. , 2010, The journals of gerontology. Series A, Biological sciences and medical sciences.

[24]  Ki-yong Kim,et al.  Fructated apolipoprotein A-I showed severe structural modification and loss of beneficial functions in lipid-free and lipid-bound state with acceleration of atherosclerosis and senescence. , 2010, Biochemical and biophysical research communications.

[25]  L. Grinberg,et al.  Human apolipoprotein A-I binds amyloid-beta and prevents Abeta-induced neurotoxicity. , 2009, The international journal of biochemistry & cell biology.

[26]  Kyung-Hyun Cho,et al.  Synthesis of reconstituted high density lipoprotein (rHDL) containing apoA-I and apoC-III: the functional role of apoC-III in rHDL , 2009, Molecules and cells.

[27]  Suzanne Craft,et al.  The role of metabolic disorders in Alzheimer disease and vascular dementia: two roads converged. , 2009, Archives of neurology.

[28]  A. Hill,et al.  High density lipoproteins bind Abeta and apolipoprotein C-II amyloid fibrils. , 2006, Journal of lipid research.

[29]  M. Hersberger,et al.  High density lipoproteins in the intersection of diabetes mellitus, inflammation and cardiovascular disease , 2004, Current opinion in lipidology.

[30]  D. Russell,et al.  Quantitation of two pathways for cholesterol excretion from the brain in normal mice and mice with neurodegeneration Published, JLR Papers in Press, June 16, 2003. DOI 10.1194/jlr.M300164-JLR200 , 2003, Journal of Lipid Research.

[31]  J. Dietschy,et al.  Cholesterol metabolism in the brain , 2001, Current opinion in lipidology.

[32]  J. Lazo,et al.  Apolipoprotein A-I directly interacts with amyloid precursor protein and inhibits A beta aggregation and toxicity. , 2001, Biochemistry.

[33]  A. Jonas,et al.  A key point mutation (V156E) affects the structure and functions of human apolipoprotein A-I. , 2000, The Journal of biological chemistry.

[34]  G. Siest,et al.  Decreased high-density lipoprotein cholesterol and serum apolipoprotein AI concentrations are highly correlated with the severity of Alzheimer’s disease☆ , 2000, Neurobiology of Aging.

[35]  A. Kumar,et al.  Alzheimer's amyloid beta interaction with normal human plasma high density lipoprotein: association with apolipoprotein and lipids. , 1998, Clinica chimica acta; international journal of clinical chemistry.

[36]  J. Thome,et al.  Advanced glycation endproducts in ageing and Alzheimer's disease , 1997, Brain Research Reviews.

[37]  B. Shilton,et al.  Role of fructose in glycation and cross-linking of proteins. , 1988, Biochemistry.

[38]  P. Matsudaira,et al.  Sequence from picomole quantities of proteins electroblotted onto polyvinylidene difluoride membranes. , 1987, The Journal of biological chemistry.

[39]  J. B. Massey,et al.  Kinetics of lipid--protein interactions: effect of cholesterol on the association of human plasma high-density apolipoprotein A-I with L-alpha-dimyristoylphosphatidylcholine. , 1979, Biochemistry.

[40]  N. Tolbert,et al.  A modification of the Lowry procedure to simplify protein determination in membrane and lipoprotein samples. , 1978, Analytical biochemistry.

[41]  Y H Chen,et al.  Determination of the secondary structures of proteins by circular dichroism and optical rotatory dispersion. , 1972, Biochemistry.

[42]  M. S. Blois,et al.  Antioxidant Determinations by the Use of a Stable Free Radical , 1958, Nature.

[43]  R. Havel,et al.  The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. , 1955, The Journal of clinical investigation.

[44]  Yuan-Han Yang,et al.  Effect of Advanced Glycation End Products on the Progression of Alzheimer's Disease. , 2019, Journal of Alzheimer's disease : JAD.

[45]  M. Pai,et al.  Apolipoprotein C-III is an amyloid-β-binding protein and an early marker for Alzheimer's disease. , 2014, Journal of Alzheimer's disease : JAD.

[46]  H. Brewer,et al.  Isolation and characterization of apolipoproteins A-I, A-II, and A-IV. , 1986, Methods in enzymology.