The recycling of apolipoprotein E in macrophages: influence of HDL and apolipoprotein A-I

The ability of apolipoprotein E (apoE) to be spared degradation in lysosomes and to recycle to the cell surface has been demonstrated by our group and others, but its physiologic relevance is unknown. In this study, we characterized apoE recycling in primary murine macrophages and probed the effects of HDL and apoA-I on this process. In cells pulsed with (125)I.apoE bound to VLDL, intact apoE was found in the chase medium for up to 24 h after the pulse. Approximately 27 +/- 5% of the apoE internalized during the pulse was recycled after 4 h of chase. Addition of apoA-I and HDL increased apoE recycling to 45 +/- 3% and 46 +/- 3%, respectively, similar to the amount of apoE recycled after pulsing the cells with (125)I.apoE.HDL. In addition, apoA-I-producing macrophages from transgenic mice showed increased apoE recycling at 4 h (38 +/- 3%). Increased ABCA1 expression potentiated apoE recycling, suggesting that recycling occurs via ABCA1. Finally, in the presence of apoA-I, recycled apoE exited the cells on HDL-like particles. These results suggest that apoE recycling in macrophages may be part of a larger signaling loop activated by HDL and directed at maximizing cholesterol losses from the cell.     

Retracted: Advances in the physiological and pathological implications of cholesterol

Cholesterol has evolved to fulfill sophisticated biophysical, cell signalling, and endocrine functions in animal systems. At the cellular level, cholesterol is found in membranes where it increases both bilayer stiffness and impermeability to water and ions. Furthermore, cholesterol is integrated into specialized lipid‐protein membrane microdomains with critical topographical and signalling functions. At the organismal level, cholesterol is the precursor of all steroid hormones, including gluco‐ and mineralo‐corticoids, sex hormones, and vitamin D, which regulate carbohydrate, sodium, reproductive, and bone homeostasis, respectively. This sterol is also the immediate precursor of bile acids, which are important for intestinal absorption of dietary lipids as well as energy homeostasis and glucose regulation. Complex mechanisms maintain cholesterol within physiological ranges and the dysregulation of these mechanisms results in embryonic or adult diseases, caused by either excessive or reduced tissue cholesterol levels. The causative role of cholesterol in these conditions has been demonstrated by genetic and pharmacological manipulations in animal models of human disease that are discussed herein. Importantly, the understanding of basic aspects of cholesterol biology has led to the development of high‐impact pharmaceutical therapies during the past century. The continuing effort to offer successful treatments for prevalent cholesterol‐related diseases, such as atherosclerosis and neurodegenerative disorders, warrants further interdisciplinary research in the coming decades.     

Neuroglia at the crossroads of homoeostasis,metabolism and signalling: evolution of the concept

Ever since Rudolf Virchow in 1858 publicly announced his apprehension of neuroglia being a true connective substance, this concept has been evolving to encompass a heterogeneous population of cells with various forms and functions. We briefly compare the 19th–20th century perspectives on neuroglia with the up-to-date view of these cells as an integral, and possibly integrating, component of brain metabolism and signalling in heath and disease. We conclude that the unifying property of otherwise diverse functions of various neuroglial cell sub-types is to maintain brain homoeostasis at different levels, from whole organ to molecular.     

Role of the kidney in regulating the metabolism of HDL in rabbits: evidence that iodination alters the catabolism of apolipoprotein A-I by the kidney

To evaluate the factors that regulate HDL catabolism in vivo, we have measured the clearance of human apoA-I from rabbit plasma by following the isotopic decay of (125)I-apoA-I and the clearance of unlabeled apoA-I using a radioimmunometric assay (RIA). We show that the clearance of unlabeled apoA-I is 3-fold slower than that of (125)I-apoA-I. The mass clearance of iodinated apoA-I, as determined by RIA, is superimposable with the isotopic clearance of (125)I-apoA-I. The data demonstrate that iodination of tyrosine residues alters the apoA-I molecule in a manner that promotes an accelerated catabolism. The clearance from rabbit plasma of unmodified apoA-I on HDL(3) and a reconstituted HDL particle (LpA-I) were very similar and about 3-4-fold slower than that for (125)I-apoA-I on the lipoproteins. Therefore, HDL turnover in the rabbit is much slower than that estimated from tracer kinetic studies. To determine the role of the kidney in HDL metabolism, the kinetics of unmodified apoA-I and LpA-I were reevaluated in animals after a unilateral nephrectomy. Removal of one kidney was associated with a 40-50% reduction in creatinine clearance rates and a 34% decrease in the clearance rate of unlabeled apoA-I and LpA-I particles. In contrast, the clearance of (125)I-labeled molecules was much less affected by the removal of a kidney; FCR for (125)I-LpA-I was reduced by <10%. The data show that the kidneys are responsible for most (70%) of the catabolism of apoA-I and HDL in vivo, while (125)I-labeled apoA-I and HDL are rapidly catabolized by different tissues. Thus, the kidney is the major site for HDL catabolism in vivo. Modification of tyrosine residues on apoA-I may increase its plasma clearance rate by enhancing extra-renal degradation pathways.     

小胶质细胞在帕金森病病理进展中的作用

帕金森病是中老年人常见的中枢神经系统退行性疾病,研究表明小胶质细胞的活化及其介导的神经炎症在帕金森病的病程进展中发挥重要作用,适度干预小胶质细胞的活化有望延缓帕金森病的进程。小胶质细胞是中枢神经系统固有的巨噬细胞,Notch信号途径可以调控小鼠外周巨噬细胞的分化及功能。Notch通路也参与调控小胶质细胞的激活、细胞因子的表达、吞噬活性的变化等,而这与活化的小胶质细胞介导的帕金森病等神经退行性疾病的病情进展相关。因此,本文将综述Notch信号途径与小胶质细胞介导的相关疾病的研究进展。     

Role of curcumin and its nanoformulations in neurotherapeutics: A comprehensive review

Curcumin, a dietary polyphenol and major constituent of Curcuma longa (Zingiberaceae), is extensively used as a spice in Asian countries. For ages, turmeric has been used in traditional medicine systems to treat various diseases, which was possible because of its anti‐inflammatory, antioxidant, anticancerous, antiepileptic, antidepressant, immunomodulatory, neuroprotective, antiapoptotic, and antiproliferative effects. Curcumin has potent antioxidant, anti‐inflammatory, antiapoptotic, neurotrophic activities, which support its plausible neuroprotective effects in neurodegenerative disease. However, there is limited information available regarding the clinical efficacy of curcumin in neurodegenerative cases. The low oral bioavailability of curcumin may be speculated as a plausible factor that limits its effects in humans. Therefore, utilization of several approaches for the enhancement of bioavailability may improve clinical outcomes. Furthermore, the use of nanotechnology and a targeted drug delivery system may improve the bioavailability of curcumin. The present review is designed to summarize the molecular mechanisms pertaining to the neuroprotective effects of curcumin and its nanoformulations.     

Iron metabolism: An emerging therapeutic target underlying the anti-Alzheimer's disease effect of ginseng

Finding neuroprotective drugs with fewer side effects and more efficacy has become a major problem as the global prevalence of Alzheimer's disease (AD) rises. Natural drugs have risen to prominence as potential medication candidates. Ginseng has a long history of use in China, and it has a wide range of pharmacological actions that can help with neurological issues. Iron loaded in the brain has been linked to AD pathogenesis. We reviewed the regulation of iron metabolism and its studies in AD and explored how ginseng might regulate iron metabolism and prevent or treat AD. Researchers utilized network pharmacology analysis to identify key factive components of ginseng that protect against AD by regulating ferroptosis. Ginseng and its active ingredients may benefit AD by regulating iron metabolism and targeting ferroptosis genes to inhibit the ferroptosis process. The results present new ideas for ginseng pharmacological studies and initiatives for further research into AD-related drugs. To provide comprehensive information on the neuroprotective use of ginseng to modulate iron metabolism, reveal its potential to treat AD, and provide insights for future research opportunities.     

Plasma metabolites related to cellular energy metabolism are altered in adults with Down syndrome and Alzheimer's disease

Down syndrome (DS) is a well‐known neurodevelopmental disorder most commonly caused by trisomy of chromosome 21. Because individuals with DS almost universally develop heavy amyloid burden and Alzheimer's disease (AD), biomarker discovery in this population may be extremely fruitful. Moreover, any AD biomarker in DS that does not directly involve amyloid pathology may be of high value for understanding broader mechanisms of AD generalizable to the neurotypical population. In this retrospective biomarker discovery study, we examined banked peripheral plasma samples from 78 individuals with DS who met clinical criteria for AD at the time of the blood draw (DS‐AD) and 68 individuals with DS who did not (DS‐NAD). We measured the relative abundance of approximately 5,000 putative features in the plasma using untargeted mass spectrometry (MS). We found significantly higher levels of a peak putatively annotated as lactic acid in the DS‐AD group (q = .014), a finding confirmed using targeted MS (q = .011). Because lactate is the terminal product of glycolysis and subsequent lactic acid fermentation, we performed additional targeted MS focusing on central carbon metabolism which revealed significantly increased levels of pyruvic (q = .03) and methyladipic (q = .03) acids in addition to significantly lower levels of uridine (q = .007) in the DS‐AD group. These data suggest that AD in DS is accompanied by a shift from aerobic respiration toward the less efficient fermentative metabolism and that bioenergetically derived metabolites observable in peripheral blood may be useful for detecting this shift.     

NAD/NADP及其介导氧化应激在神经退行性疾病中的作用

神经退行性疾病如阿尔茨海默病、帕金森病、亨廷顿病等疾病的发生与氧化应激紧密相关。NAD和NADP是维持氧化系统和抗氧化系统平衡的两个关键物质。NAD和NADP的生物合成和降解有多种途径,参与其生物途径的物质如NAMPT、NADK、PARP1、SIRT1、CD38等,均报道在神经退行性疾病发挥一定的作用。因此,本文分别从NAD和NADP的合成和降解途径中的一些关键物质出发,结合氧化应激总结并探讨它们在神经退行性疾病的作用,以期为临床治疗神经退行性疾病提供新思路。     

Combined application of rapamycin and atorvastatin improves lipid metabolism in apolipoprotein E-deficient mice with chronic kidney disease

Atherosclerosis arising from the pro-inflammatory conditions associated with chronic kidney disease (CKD) increases major cardiovascular morbidity and mortality. Rapamycin (RAPA) is known to inhibit atherosclerosis under CKD and non-CKD conditions, but it can cause dyslipidemia; thus, the co-application of lipid-lowering agents is recommended. Atorvastatin (ATV) has been widely used to reduce serum lipids levels, but its synergistic effect with RAPA in CKD remains unclear. Here, we analyzed the effect of their combined treatment on atherosclerosis stimulated by CKD in apolipoprotein E-deficient (ApoE^−/−) mice. Oil Red O staining revealed that treatment with RAPA and RAPA＋ ATV, but not ATV alone, significantly decreased the atherosclerotic lesions in the aorta and aortic sinus, compared to those seen in the control (CKD) group. The co-administration of RAPA and ATV improved the serum lipid profile and raised the expression levels of proteins involved in reverse cholesterol transport (LXRα, CYP7A1, ABCG1, PPARγ, ApoA1) in the liver. The CKD group showed increased levels of various genes encoding atherosclerosis-promoting cytokines in the spleen (Tnf-α, Il-6 and Il-1β) and aorta (Tnf-α and Il-4), and these increases were attenuated by RAPA treatment. ATV and RAPA＋ATV decreased the levels of Tnf-α and Il-1β in the spleen, but not in the aorta. Together, these results indicate that, in CKD-induced ApoE^−/− mice, RAPA significantly reduces the development of atherosclerosis by regulating the expression of inflammatory cytokines and the co-application of ATV improves lipid metabolism.     

Insights into the Role of Erythrina corallodendron L. in Alzheimer's Disease: in Vitro and in Silico Approach

Alzheimer's disease (AD) is a major health problem. Cholinergic transmission is greatly affected in AD. Phytochemical investigation of the alkaloid rich fraction (AF) of Erythrina corallodendron L leaves resulted in isolation of five known alkaloids: erysodine, erythrinine, 8-oxoerythrinine, erysovine N-oxide and erythrinine N-oxide. In this study, eysovine N-oxide was reported for the second time in nature. AF was assayed for cholinesterase inhibition at the concentration of 100 μg mL⁻¹. AF showed a higher percent inhibition for butyrylcholinesterase enzyme (BuChE) (83.28 %) compared to acetylcholinesterase enzyme (AChE) (64.64 %). The isolated alkaloids were also assayed for their anti-BuChE effect. In-silico docking study was done for the isolated compounds at the binding sites of AChE and BuChE to determine their binding pattern and interactions, also molecular dynamics were estimated for the compound displaying the best fit for AChE and BuChE. In addition, ADME parameters and toxicity were predicted for the isolated alkaloids compared to donepezil.     

甲基乙二醛在阿尔茨海默病中的作用

糖酵解毒性副产物甲基乙二醛（methylglyoxal,MG）以其高反应活性在阿尔茨海默病（Alzheimer''s disease,AD）发生发展过 程中起到了重要的作用。MG 在AD病人脑中累积并促进beta淀粉样蛋白(beta-amyloid peptide,A beta)的产生和寡聚。大量累积的MG 通 过形成晚期糖基化终末产物(advanced glycosylation end products,AGEs)加剧了神经元中tau 蛋白的过度磷酸化。研究还发现MG 和AGEs 均参与了AD 脑中活性氧（reactive oxygen species,ROS）的产生和炎症的发生发展。本文总结了MG 在AD 病理过程中 的作用,并加以综述。     

CC类趋化因子配体5与冠状动脉粥样硬化的相关性研究

目的:探讨CC类趋化因子配体5(CC chemokine ligand-5,CCL5)的表达水平与冠状动脉粥样硬化(Atherosclerosis,AS)严重程度之间的相关性。方法:将颈动脉粥样硬化狭窄(70%)行颈动脉内膜切除术的5例手术标本作为AS组,尸检无动脉粥样硬化的正常颈动脉3例作为对照组。应用免疫组织化学、Western blot检测AS组和对照组中CCL5的表达。收集110例冠状动脉造影术患者,根据Gensini评分分为对照组(Gensini评分=0分,n=27),轻微病变组(0Gensini评分≤20,n=32)和严重病变组(Gensini评分20,n=51)。收集各组的临床基线资料(包括年龄、性别、血压、血脂、血糖等),ELISA方法检测各组血浆中CCL5表达水平,并分析各危险因素、CCL5表达水平与Gensini评分之间的相关性。结果:颈AS组AS组织中CCL5蛋白的表达明显高于正常颈动脉组(P0.05),冠心病患者血浆CCL5水平明显高于对照组,差异具有统计学意义(P0.05)。对照组、轻微病变组和严重病变组在性别、吸烟史、收缩压、舒张压、血糖及血浆CCL5的表达上存在显著的差别。相关性分析显示舒张压、血糖及血浆CCL5表达水平与Gensini评分间呈显著正相关(r=0.276、0.418、0.519,P0.05)。以Gensini评分为因变量,性别、年龄、吸烟史、收缩压、舒张压、LDL-C、HDL-C、血糖、血浆CCL5为自变量建立多元逐步线性回归模型,结果提示血浆CCL5为Gensini评分的独立预测因子(B值为8.775;P值为0.000)。结论:血浆CCL5水平与冠状动脉粥样硬化病变程度呈正相关,可能作为AS程度的独立预测因子。     

Somatostatin in Alzheimer's disease: A new Role for an Old Player

The amyloid beta (Aβ) peptide is central to the pathogenesis of Alzheimer's disease (AD). Insights into Aβ-interacting proteins are critical for understanding the molecular mechanisms underlying Aβ-mediated toxicity. We recently undertook an in-depth in vitro interrogation of the Aβ1–42 interactome using human frontal lobes as the biological source material and taking advantage of advances in mass spectrometry performance characteristics. These analyses uncovered the small cyclic neuropeptide somatostatin (SST) to be the most selectively enriched binder to oligomeric Aβ1–42. Subsequent validation experiments revealed that SST interferes with Aβ fibrillization and promotes the formation of Aβ assemblies characterized by a 50–60 kDa SDS-resistant core. The distributions of SST and Aβ overlap in the brain and SST has been linked to AD by several additional observations. This perspective summarizes this body of literature and draws attention to the fact that SST is one of several neuropeptide hormones that acquire amyloid properties before their synaptic release. The latter places the interaction between SST and Aβ among an increasing number of observations that attest to the ability of amyloidogenic proteins to influence each other. A model is presented which attempts to reconcile existing data on the involvement of SST in the AD etiology.     

Regulation of autophagy by polyphenols: Paving the road for treatment of neurodegeneration

In the present paper, we will discuss on the importance of autophagy in the central nervous system, and outline the relation between autophagic pathways and the pathogenesis of neurodegenerative disorders. The potential therapeutic benefits of naturally occurring phytochemicals as pharmacological modulators of autophagy will also be addressed. Our findings provide renewed insight on the molecular modes of protection by polyphenols, which is likely to be at least in part mediated not only by their potent antioxidant and anti-inflammatory effects, but also through modulation of autophagic processes to remove the aberrant protein aggregates.     

Role of aggregation conditions in structure, stability, and toxicity of intermediates in the Abeta fibril formation pathway

beta-amyloid peptide (Abeta) is one of the main protein components of senile plaques associated with Alzheimer's disease (AD). Abeta readily aggregates to forms fibrils and other aggregated species that have been shown to be toxic in a number of studies. In particular, soluble oligomeric forms are closely related to neurotoxicity. However, the relationship between neurotoxicity and the size of Abeta aggregates or oligomers is still under investigation. In this article, we show that different Abeta incubation conditions in vitro can affect the rate of Abeta fibril formation, the conformation and stability of intermediates in the aggregation pathway, and toxicity of aggregated species formed. When gently agitated, Abeta aggregates faster than Abeta prepared under quiescent conditions, forming fibrils. The morphology of fibrils formed at the end of aggregation with or without agitation, as observed in electron micrographs, is somewhat different. Interestingly, intermediates or oligomers formed during Abeta aggregation differ greatly under agitated and quiescent conditions. Unfolding studies in guanidine hydrochloride indicate that fibrils formed under quiescent conditions are more stable to unfolding in detergent than aggregation associated oligomers or Abeta fibrils formed with agitation. In addition, Abeta fibrils formed under quiescent conditions were less toxic to differentiated SH-SY5Y cells than the Abeta aggregation associated oligomers or fibrils formed with agitation. These results highlight differences between Abeta aggregation intermediates formed under different conditions and provide insight into the structure and stability of toxic Abeta oligomers.     

Differential lipid metabolism in monocytes and macrophages: influence of cholesterol loading

The influence of the hypercholesterolemia associated with atherosclerosis on monocytes is poorly understood. Monocytes are exposed to high concentrations of lipids, particularly cholesterol and lysophosphatidylcholine (lyso-PC). Indeed, in line with recent reports, we found that monocytes accumulate cholesteryl esters (CEs) in hypercholesterolemic mice, demonstrating the need for studies that analyze the effects of lipid accumulation on monocytes. Here we analyze the effects of cholesterol and lyso-PC loading in human monocytes and macrophages. We found that cholesterol acyltransferase and CE hydrolase activities are lower in monocytes. Monocytes also showed a different expression profile of cholesterol influx and efflux genes in response to lipid loading and a different pattern of lyso-PC metabolism. In monocytes, increased levels of CE slowed the conversion of lyso-PC into PC. Interestingly, although macrophages accumulated glycerophosphocholine, phosphocholine was the main water-soluble choline metabolite being generated in monocytes, suggesting a role for mono- and diacylglycerol in the chemoattractability of these cells. In summary, monocytes and macrophages show significant differences in lipid metabolism and gene expression profiles in response to lipid loading. These findings provide new insights into the mechanisms of atherosclerosis and suggest potentials for targeting monocyte chemotactic properties not only in atherosclerosis but also in other diseases.