Genome-wide association study of LDL-cholesterol over ApoB ratio

Genome-Wide Association Study analytical (GWAS) methods were applied in a large biracial sample of individuals to investigate variation across the genome for its association with a surrogate low-density lipoprotein (LDL) particle size phenotype, the ratio of LDL-cholesterol level over ApoB level. Genotyping was performed on the Affymetrix 6.0 GeneChip with approximately one million single nucleotide polymorphisms (SNPs). The ratio of LDL cholesterol to ApoB was calculated, and association tests used multivariable linear regression analysis with an additive genetic model after adjustment for the covariates sex, age and BMI. Association tests were performed separately in African Americans and Caucasians. There were 9,562 qualified individuals in the Caucasian group and 3,015 qualified individuals in the African American group. Overall, in Caucasians two statistically significant loci were identified as being associated with the ratio of LDL-cholesterol over ApoB: rs10488699 (p<5 x10-8, 11q23.3 near BUD13) and the SNP rs964184 (p<5 x10-8 11q23.3 near ZNF259). We also found rs12286037 ((p<4x10-7) (11q23.3) near APOA5/A4/C3/A1 with suggestive associate in the Caucasian sample. In exploratory analyses, a difference in the pattern of association between individuals taking and not taking LDL-cholesterol lowering medications was observed. Individuals who were not taking medications had smaller p-value than those taking medication. In the African-American group, there were no significant (p<5x10-8) or suggestive associations (p<4x10-7) with the ratio of LDL-cholesterol over ApoB after adjusting for age, BMI, and sex and comparing individuals with and without LDL-cholesterol lowering medication. Conclusions: There were significant and suggestive associations between SNP genotype and the ratio of LDL-cholesterol to ApoB in Caucasians, but these associations may be modified by medication treatment.^

Direct Binding of Occupied Urokinase Receptor (uPAR) to LDL Receptor-related Protein Is Required for Endocytosis of uPAR and Regulation of Cell Surface Urokinase Activity

Low-density lipoprotein receptor-related protein (LRP) mediates internalization of urokinase:plasminogen activator inhibitor complexes (uPA:PAI-1) and the urokinase receptor (uPAR). Here we investigated whether direct interaction between uPAR, a glycosyl-phosphatidylinositol–anchored protein, and LRP, a transmembrane receptor, is required for clearance of uPA:PAI-1, regeneration of unoccupied uPAR, activation of plasminogen, and the ability of HT1080 cells to invade extracellular matrix. We found that in the absence of uPA:PAI-1, uPAR is randomly distributed along the plasma membrane, whereas uPA:PAI-1 promotes formation of uPAR-LRP complexes and initiates redistribution of occupied uPAR to clathrin-coated pits. uPAR-LRP complexes are endocytosed via clathrin-coated vesicles and traffic together to early endosomes (EE) because they can be coimmunoprecipitated from immunoisolated EE, and internalization is blocked by depletion of intracellular K+. Direct binding of domain 3 (D3) of uPAR to LRP is required for clearance of uPA-PAI-1–occupied uPAR because internalization is blocked by incubation with recombinant D3. Moreover, uPA-dependent plasmin generation and the ability of HT1080 cells to migrate through Matrigel-coated invasion chambers are also inhibited in the presence of D3. These results demonstrate that GPI-anchored uPAR is endocytosed by piggybacking on LRP and that direct binding of occupied uPAR to LRP is essential for internalization of occupied uPAR, regeneration of unoccupied uPAR, plasmin generation, and invasion and migration through extracellular matrix.

Efeito das gorduras interesterificadas sobre o desenvolvimento da lesão aterosclerótica em camundongos knockout para o receptor de LDL

Nas últimas décadas, diversos estudos têm demonstrado os efeitos nocivos dos ácidos graxos trans à saúde. Consequentemente, diversas agências reguladoras de saúde e sociedades responsáveis pela elaboração de diretrizes nutricionais recomendaram a redução do consumo desses ácidos graxos. Deste modo, a indústria de alimentos vem adequando seus produtos a fim de substituir os ácidos graxos trans por gorduras interesterificadas, porém seus efeitos sobre o desenvolvimento da aterosclerose não foram ainda totalmente elucidados. Portanto, o objetivo deste estudo foi avaliar o efeito de gorduras interesterificadas contendo principalmente ácido graxo palmítico ou esteárico sobre o desenvolvimento da aterosclerose. Desta forma, camundongos knockout para o receptor de LDL (LDLr-KO) recém-desmamados foram alimentados por 16 semanas com dietas hiperlipídicas (40% do valor calórico total sob forma de gordura) contendo principalmente ácidos graxos poli-insaturados (POLI), trans (TRANS), palmítico (PALM), palmítico interesterificado (PALM INTER), esteárico (ESTEAR) ou esteárico interesterificado (ESTEAR INTER) para determinação de concentrações plasmáticas de colesterol total e triglicérides; perfil de lipoproteínas; conteúdo de lípides (Oil Red O) e colágeno (Picrosirius Red) e infiltrado de macrófagos (imuno-histoquímica) na área de lesão aterosclerótica; expressão e conteúdo proteico de citocinas na aorta; dosagem das citocinas secretadas por macrófagos de peritônio estimulados ou não com lipopolissacarídeo (LPS); efluxo celular de colesterol mediado pela apo-AI e HDL2. Os resultados mostraram que os animais que consumiram a gordura interesterificada contendo ácido palmítico (PALM INTER) desenvolveram importante lesão aterosclerótica em comparação aos grupos PALM, ESTEAR, ESTEAR INTER e POLI, resultados confirmados pelo conteúdo de colágeno na lesão. Apesar do processo de interesterificação não ter alterado as concentrações plasmáticas de lípides, conforme verificado entre os grupos PALM vs PALM INTER e ESTEAR vs ESTEAR INTER, o acúmulo de colesterol na partícula de LDL foi similar entre os grupos PALM INTER e TRANS. Além desse efeito sobre o perfil de lipoproteínas, macrófagos do peritônio de camundongos que consumiram PALM INTER secretaram significativamente mais IL-1beta, IL-6 e MCP-1 em comparação aos demais grupos. Esse efeito pró-inflamatório foi confirmado na aorta, onde se observou maior expressão de TNF-alfa e IL-1beta para o grupo PALM INTER em comparação a PALM. Tal insulto inflamatório foi similar ao provocado por TRANS. Esses efeitos deletérios do PALM INTER podem ser parcialmente atribuídos ao acúmulo de colesterol nos macrófagos, promovido pelo prejuízo no efluxo de colesterol mediado pela apo-AI e HDL2, bem como aumento da expressão de receptores envolvidos na captação de LDL modificada (Olr-1) e diminuição daqueles envolvidos na remoção intracelular de colesterol (Abca1 e Nr1h3) na parede arterial. Como conclusão, as gorduras interesterificadas contendo ácido palmítico favorecem o acúmulo de colesterol nas partículas de LDL e em macrófagos, ativando o processo inflamatório, o que conjuntamente contribuiu para maior desenvolvimento de lesão aterosclerótica

Effects of LDL-immunoapheresis on plasma concentrations of vitamin E and carotenoids in patients with familial hypercholesterolemia

Recently very potent extracorporeal cholesterol-lowering treatment options have become available for patients with hypercholesterolemia. LDL immunoapheresis treatment selectively removes LDL and lipoprotein(a) from the circulation. Since LDL is the major carrier of lipophilic antioxidants in plasma, the purpose of the present study was to assess the effects of a single LDL apheresis treatment on plasma concentrations of tocopherols (alpha- and gamma-tocopherol) and carotenoids (alpha- and beta-carotene, zeaxanthin, cryptoxanthin, canthaxanthin, lycopene, and retinol). Plasma antioxidant concentrations were determined by HPLC in 7 patients with familial hypercholesterolemia before and after LDL immunoapheresis treatment. Plasma concentrations of both alpha- and gamma-tocopherol and the different carotenoids were significantly reduced by LDL apheresis. However, when standardized for cholesterol to adjust for cholesterol removal, alpha- and gamma-tocopherol, retinol, and the more polar carotenoids lutein and zeaxanthin increased in response to apheresis treatment, while the more unpolar carotenoids such as beta-carotene and lycopene did not change. These data demonstrate that a single LDL immunoapheresis treatment affects tocopherols and individual carotenoids differently. This may be explained by differences in chemical structure and preferential association with different lipoproteins. These results further imply that tocopherols, lutein, zeaxanthin, and retinol, are associated in part with lipoproteins and other carriers such as retinol-binding protein that are not removed during apheresis treatment. (C) 2004 Wiley-Liss, Inc.

Ceramides reduce CD36 cell surface expression and oxidised LDL uptake by monocytes and macrophages

Oxidised LDL accumulates in macrophages following scavenger receptor (SR) uptake. The expression of the SR, CD36, is increased by oxidised LDL. The signalling molecule, ceramide, can modulate intracellular peroxides and increase lipid peroxidation. Ceramide also accumulates in atherosclerotic plaques. Thus, we have examined whether ceramide can modulate CD36 expression and function in human monocyte/macrophages. Addition of synthetic short chain ceramides or the action of sphingomyelinase to generate physiological long chain ceramides in situ caused significant reductions in CD36 expression by monocytes/macrophages which was not due to inhibition of mRNA expression. Inhibition of proteasomal degradation using lactacystin had no effect on CD36 expression, however, flow cytometric analysis of permeabilised cells suggested an intracellular trafficking blockade. Ceramide treated monocytes/macrophages showed dose dependent reduction in oxidised LDL uptake. Taken together, it is suggested that ceramide blocks the transport of CD36 to the membrane of monocytes/macrophages, thereby preventing uptake of oxidised LDL. © 2006 Elsevier Inc. All rights reserved.

Homocysteine from endothelial cells promotes LDL nitration and scavenger receptor uptake

We recently reported that methionine-loaded human umbilical vein endothelial cells (HUVECs) exported homocysteine (Hcy) and were associated with hydroxyl radical generation and oxidation of lipids in LDL. Herein we have analysed the Hcy-induced posttranslational modifications (PTMs) of LDL protein. PTMs have been characterised using electrophoretic mobility shift, protein carbonyl ELISA, HPLC with electrochemical detection and Western blotting of 3-nitrotyrosine, and LDL uptake by scavenger receptors on monocyte/macrophages. We have also analysed PTMs in LDL isolated from rheumatoid (RA) and osteo-(OA) arthritis patients with cardiovascular disease (CVD). While reagent Hcy (<50 μM) promoted copper-catalysed LDL protein oxidation, Hcy released from methionine-loaded HUVECs promoted LDL protein nitration. In addition, LDL nitration was associated with enhanced monocyte/macrophage uptake when compared with LDL oxidation. LDL protein nitration and uptake by monocytes, but not carbonyl formation, was elevated in both RA and OA patients with CVD compared with disease-matched patients that had no evidence of CVD. Moreover, a direct correlation between plasma total Hcy (tHcy) and LDL uptake was observed. The present studies suggest that elevated plasma tHcy may promote LDL nitration and increased scavenger receptor uptake, providing a molecular mechanism that may contribute to the clinical link between CVD and elevated plasma tHcy. © 2005 Elsevier Inc. All rights reserved.

Oxidative modification of a specific apolipoprotein B lysine residue confers altered receptor specificity on LDL

During inflammation, many cell types release reactive oxygen species (ROS) via the respiratory burst. These ROS are potent oxidants of LDL and its major protein, apolipoprotein B. Whilst native LDL is taken up by endothelial cells via a feedback controlled receptor-regulated process, oxidative modification of LDL renders it a ligand for many scavenger receptors. Scavenger receptors include CD-36, LOX-1 and the prototypic macrophage SR A I/II, all of which are variably expressed. Uncontrolled uptake of oxidised LDL is implicated in the pathogenesis of atherosclerosis. In addition, oxidised LDL increases CCR2 protein and mRNA expression on monocytes, and thus may contribute to monocyte retention and perpetuation in inflammatory, unstable atherosclerotic lesions. However, little data are available on the effects of specific minor modifications to apolipoprotein B. In order to identify the sequence specificity and nature of oxidative modifications which confer altered properties on LDL, we have investigated the effects of modified peptides (which correspond to the putative LDLR binding domain) on LDL uptake by HUVECs and U937 monocytes.

Validation of a novel ELISA for measurement of MDA-LDL in human plasma

The involvement of oxidatively modified low density lipoprotein (LDL) in the development of CHD is widely described. We have produced two antibodies, recognizing the lipid oxidation product malondialdehyde (MDA) on whole LDL or ApoB-100. The antibodies were utilized in the development of an ELISA for quantitation of MDA-LDL in human plasma. Intra- and inter-assay coefficients of variation (% CV) were measured as 4.8 and 7.7%, respectively, and sensitivity of the assay as 0.04 μg/ml MDA-LDL. Recovery of standard MDA-LDL from native LDL was 102%, indicating the ELISA to be specific with no interference from other biomolecules. Further validation of the ELISA was carried out against two established methods for measurement of lipid peroxidation products, MDA by HPLC and F2-isoprostanes by GC-MS. Results indicated that MDA-LDL is formed at a later stage of oxidation than either MDA or F2- isoprostanes. In vivo analysis demonstrated that the ELISA was able to determine steady-state concentrations of plasma MDA-LDL (an end marker of lipid peroxidation). A reference range of 34.3 ± 8.8 μg/ml MDA-LDL was established for healthy individuals. Further, the ELISA was used to show significantly increased plasma MDA-LDL levels in subjects with confirmed ischemic heart disease, and could therefore possibly be of benefit as a diagnostic tool for assessing CHD risk. © 2003 Elsevier Inc.

Oxidative LDL modification is increased in vascular dementia and is inversely associated with cognitive performance

It is not known whether the association between increased plasma homocysteine (Hcy) associated with LDL modification and propensity for LDL uptake by macrophages in cardiovascular disease patients holds true in vascular dementia (VaD). Plasma from 83 subjects diagnosed with Alzheimer's disease (AD), VaD, mild cognitive impairment (MCI) and from controls was analysed to examine (1) whether LDL isolated from the plasma of VaD is biochemically and functionally distinct from that isolated from AD, MCI or controls; and (2) whether such biomarkers of LDL phenotype are related to plasma folate levels, Hcy levels and/or to disease severity. Folate and vitamin B6 levels were significantly lower in VaD subjects than in controls. VaD-LDL showed increased protein carbonyl content (p <0.05) and was more susceptible to scavenging by macrophages (p <0.05) than AD- or control-LDL. Patients from the VaD cohort were more prevalent in the lowest tertile for HDL:LDL and the upper tertile for LDL oxidation; the combined parameters of HDL cholesterol, LDL oxidation and scavenging by macrophages show 87% sensitivity towards VaD detection. The association between folate deficiency, LDL modification and dysfunction in VaD but not in AD may provide a novel biomarker assessment to discriminate between the diseases.

A comparison of five lipid extraction solvent systems for lipidomic studies of human LDL

Lipidome profile of fluids and tissues is a growing field as the role of lipids as signaling molecules is increasingly understood, relying on an effective and representative extraction of the lipids present. A number of solvent systems suitable for lipid extraction are commonly in use, though no comprehensive investigation of their effectiveness across multiple lipid classes has been carried out. To address this, human LDL from normolipidemic volunteers was used to evaluate five different solvent extraction protocols [Folch, Bligh and Dyer, acidified Bligh and Dyer, methanol (MeOH)-tert-butyl methyl ether (TBME), and hexane-isopropanol] and the extracted lipids were analyzed by LC-MS in a high-resolution instrument equipped with polarity switching. Overall, more than 350 different lipid species from 19 lipid subclasses were identified. Solvent composition had a small effect on the extraction of predominant lipid classes (triacylglycerides, cholesterol esters, and phosphatidylcholines). In contrast, extraction of less abundant lipids (phosphatidylinositols, lyso-lipids, ceramides, and cholesterol sulfates) was greatly influenced by the solvent system used. Overall, the Folch method was most effective for the extraction of a broad range of lipid classes in LDL, although the hexane-isopropanol method was best for apolar lipids and the MeOH-TBME method was suitable for lactosyl ceramides. Copyright © 2013 by the American Society for Biochemistry and Molecular Biology, Inc.

Oxidised LDL-lipids increase beta amyloid production by SH-SY5Y cells through glutathione depletion and lipid raft formation

Elevated total cholesterol in midlife has been associated with increased risk of dementia in later life. We have previously shown that low-density lipoprotein (LDL) is more oxidized in the plasma of dementia patients, although total cholesterol levels are not different from those of age-matched controls. β-Amyloid (Aβ) peptide, which accumulates in Alzheimer disease (AD), arises from the initial cleavage of amyloid precursor protein by β-secretase-1 (BACE1). BACE1 activity is regulated by membrane lipids and raft formation. Given the evidence for altered lipid metabolism in AD, we have investigated a mechanism for enhanced Aβ production by SH-SY5Y neuronal-like cells exposed to oxidized LDL (oxLDL). The viability of SH-SY5Y cells exposed to 4 μg oxLDL and 25 μM 27-hydroxycholesterol (27OH-C) was decreased significantly. Lipids, but not proteins, extracted from oxLDL were more cytotoxic than oxLDL. In parallel, the ratio of reduced glutathione (GSH) to oxidized glutathione was decreased at sublethal concentrations of lipids extracted from native and oxLDL. GSH loss was associated with an increase in acid sphingomyelinase (ASMase) activity and lipid raft formation, which could be inhibited by the ASMase inhibitor desipramine. 27OH-C and total lipids from LDL and oxLDL independently increased Aβ production by SH-SY5Y cells, and Aβ accumulation could be inhibited by desipramine and by N-acetylcysteine. These data suggest a mechanism whereby oxLDL lipids and 27OH-C can drive Aβ production by GSH depletion, ASMase-driven membrane remodeling, and BACE1 activation in neuronal cells. © 2014 The Authors.

Angiopoietin-2 confers Atheroprotection in apoE-/- mice by inhibiting LDL oxidation via nitric oxide

Atherosclerosis is promoted by a combination of hypercholesterolemia and vascular inflammation. The function of Angiopoietin (Ang)-2, a key regulator of angiogenesis, in the maintenance of large vessels is unknown. A single systemic administration of Ang-2 adenovirus (AdAng-2) to apoE-/- mice fed a Western diet significantly reduced atherosclerotic lesion size 8 40%) and oxidized LDL and macrophage content of the plaques. These beneficial effects were abolished by the inhibition of nitric oxide synthase (NOS). In endothelial cells, endothelial NOS activation per se inhibited LDL oxidation and Ang-2 stimulated NO release in a Tie2-dependent manner to decrease LDL oxidation. These findings demonstrate a novel atheroprotective role for Ang-2 when endothelial cell function is compromised and suggest that growth factors, which stimulate NO release without inducing inflammation, could offer atheroprotection.

LDL-Lipids from patients with hypercholesterolaemia and Alzheimer's disease are inflammatory to microvascular endothelial cells:mitigation by statin intervention

Elevated LDL concentration in mid-life increases the risk of developing Alzheimer's disease (AD) in later life. Increased oxidative modification (oxLDL) and nitration is observed during dementia and hypercholesterolemia. We investigated the hypothesis that statin intervention in mid-life mitigates the inflammatory effects of oxLDL on the microvasculature. Human microvascular endothelial cells (HMVEC) were maintained on transwells to mimic the microvasculature and exposed to patient and control LDL. Blood was obtained from statin-naïve, normo- and hyperlipidaemic subjects, AD with vascular dementia (AD-plus) and AD subjects (n=10/group) at baseline. Only hyperlipidaemic subjects with normal cognitive function received 40mg simvastatin intervention/day for three months. Blood was re-analysed from normo- and hyper-lipidaemic subjects after three months. LDL isolated from statin-naïve hyperlipidaemic, AD and AD-plus subjects was more oxidised (agarose gel electrophoretic mobility, protein carbonyl content and 8-isoprostane F2α) compared to control subjects. Statin intervention decreased protein carbonyls (2.5±0.4 Vs 3.95±0.2nmol/mg; P<0.001) and 8-isoprostane F2α (30.4±4.0 pg/ml Vs 43.5±8.42 pg/ml; P<0.05). HMVEC treatment with LDL-lipids from hyperlipidaemic, AD and AD-plus subjects impaired endothelial tight junction expression and decreased total glutathione levels (AD; 18.61±1.3, AD-plus; 16.5±0.7nmol/mg protein) compared to untreated cells (23.8±1.2 vs nmol/mg protein). Basolateral IL-6 secretion was increased by LDL-lipids from hyperlipidaemic (78.4±1.9 pg/ml), AD (63.2±5.9 pg/ml) and AD-plus (80.8±0.9 pg/ml) groups compared to healthy subject lipids (18.6±3.6 pg/ml). LDL-Lipids isolated after statin intervention did not affect endothelial function. In summary, LDL-lipids from hypercholesterolaemic, AD and AD-plus patients are inflammatory to HMVEC. In vivo intervention with statins reduces the damaging effects of LDL-lipids on HMVEC.

Oxidised LDL lipids, statins and a blood-brain barrier

Elevated cholesterol in mid-life has been associated with increased risk of dementia in later life. We have previously shown that low density lipoprotein (LDL) is more oxidised in the plasma of dementia patients although total cholesterol levels remained unchanged. Increased systemic oxidative modification (oxLDL) and nitration is also observed during hypercholesterolemia. We have investigated the hypothesis that disruption of blood brain barrier (BBB) function by oxLDL and their lipids may increase risk of neurodegeneration in later life and that statin intervention can mitigate the effects of hyperlipidaemia in mid-life. LDL isolated from statin-naïve hypercholesterolaemic subjects had higher mobility by agarose gel electrophoresis (Rf;0.53±0.06) and 8-isoprostane F2α concentration (43.5±8.42pg/ml) compared to control subjects (Rf; 0.46±0.05 and 24.2±5.37pg/ml respectively; p<0.05). Compared to HMVEC treatment with the LDL-lipids (5μM) from normolipidaemic subjects, LDL-lipids from hypercholesterolaemic subjects increased barrier permeability (103.4±12.5 Ωcm2 v 66.7±7.3 Ωcm2,P<0.01) and decreased cellular glutathione levels (18.5nmol/mg v 12.3nmol/mg) compared to untreated cells (26.2±3.6nmol/mg). LDL-lipids isolated from normolipidaemic subjects shows reduced risk to damage a BBB model compared with LDL-lipids from hypercholesterolaemic subjects. Moreover, a three month statin-intervention reduced the propensity for LDL-lipids from subjects with hyperlipidaemia to damage HMVEC. Post-statin treatment the cytotoxic and pro-inflammatory effects of LDL lipids disappeared. These data support the hypothesis that in vivo intervention with statins modifies LDL lipid oxidation, exerting a protective effect against in microvascular damage independent of cholesterol concentration.

Oxidised LDL-lipids alter redox ratio, lipid raft formation and increase amyloid beta production by SHSY-5Y cells

Elevated cholesterol in mid-life has been associated with increased risk of dementia in later life. We have previously shown that low density lipoprotein (LDL) is more oxidised in the plasma of dementia patients although total cholesterol levels remained unchanged [1]. We have investigated the hypothesis that amyloid beta production and neurodegeneration can be driven by oxidised lipids derived from LDL following the loss of blood brain barrier integrity with ageing. Therefore, we have investigated amyloid beta formation in SHSY5Y cells treated with LDL, minimally modified (ox) LDL, and lipids extracted from both forms of LDL. LDL-treated SHSY-5Y cell viability was not significantly decreased with up to 8 μg LDL/2 × 104 cells compared to untreated cells. However, 8 μg oxLDL protein/2 × 104 cells decreased the cell viability significantly by 33.7% (P < 0.05). A more significant decrease in cell viability was observed when treating cells with extracted lipids from 8 μg of LDL (by 32.7%; P < 0.01) and oxLDL (by 41%; P < 0.01). In parallel, the ratio of reduced to oxidised GSH was decreased; GSH concentrations were significantly decreased following treatment with 0.8 μg/ml oxLD-L (7.35 ± 0.58;P < 0.01), 1.6 μg/ml (5.27 ± 0.23; P < 0.001) and 4 μg/ml (5.31 ± 0.31; P < 0.001). This decrease in redox potential was associated with an increase acid sphingomyelinase activity and lipid raft formation which could be inhibited by desipramine; SHSY5Y cells treated with oxLDL, and lipids from LDL and oxLDL for 16 h showed significantly increased acid sphingomyelinase activity (5.32 ± 0.35; P < 0.05, 5.21 ± 0.6; P < 0.05, and 5.58 ± 0.44; P < 0.01, respectively) compared to control cells (2.96 ± 0.34). As amyloid beta production is driven by the activity of beta secretase and its association with lipid rafts, we investigated whether lipids from ox-LDL can influence amyloid beta by SHSY-5Y cells in the presence of oxLDL. Using ELISA and Western blot, we confirmed that secretion of amyloid beta oligomers is increased by SHSY-5Y cells in the presence of oxLDL lipids. These data suggest a mechanism whereby LDL, and more significantly oxLDL lipids, can drive amyloid beta production and cytotoxicity in neuronal cells. [1] Li L, Willets RS, Polidori MC, Stahl W, Nelles G, Sies H, Griffiths HR. Oxidative LDL modification is increased in vascular dementia and is inversely associated with cognitive performance. Free Radic Res. 2010 Mar; 44(3): 241–8.