Alzheimer Disease: Yan SD

Yan SD, Bierhaus A, Nawroth PP, Stern DM. · Department of Pathology, College of Physicians & Surgeons of Columbia University, New York City, NY, USA. · J Alzheimers Dis. · Pubmed #19387116 No free full text.

Abstract: Receptor for Advanced Glycation Endproducts (RAGE) is a multiligand member of the immunoglobulin superfamily of cell surface molecules which serves as a receptor for amyloid-beta peptide (Abeta) on neurons, microglia, astrocytes, and cells of vessel wall. Increased expression of RAGE is observed in regions of the brain affected by Alzheimer's disease (AD), and Abeta-RAGE interaction in vitro leads to cell stress with the generation of reactive oxygen species and activation of downstream signaling mechanisms including the MAP kinase pathway. RAGE-mediated activation of p38 MAP kinase in neurons causes Abeta-induced inhibition of long-term potentiation in slices of entorhinal cortex. Increased expression of RAGE in an Abeta-rich environment, using transgenic mouse models, accelerates and accentuates pathologic, biochemical, and behavioral abnormalities compared with mice overexpressing only mutant amyloid-beta protein precursor. Interception of Abeta interaction with RAGE, by infusion of soluble RAGE, decreases Abeta content and amyloid load, as well as improving learning/memory and synaptic function, in a murine transgenic model of Abeta accumulation. These data suggest that RAGE may be a therapeutic target for AD.

Chen X, Walker DG, Schmidt AM, Arancio O, Lue LF, Yan SD. · Department of Neurology and Neurosurgery,North Shore-LIJ Health System, NY, USA. · Curr Mol Med. · Pubmed #18331231 No free full text.

Abstract: This review focuses on the current findings regarding interaction between amyloid beta peptide (Abeta) and receptor for advanced glycation endproducts (RAGE) and its roles in the pathogenesis of Alzheimer's disease (AD). As a ubiquitously expressed cell surface receptor, RAGE mediates the effects of Abeta on microglia, blood-brain barrier (BBB) and neurons through activating different signaling pathways. Data from autopsy brain tissues, in vitro cell cultures and transgenic mouse models suggest that Abeta-RAGE interaction exaggerates neuronal stress, accumulation of Abeta, impaired learning memory, and neuroinflammation. Blockade of RAGE protects against Abeta-mediated cellular perturbation. These findings may have an important therapeutic implication for neurodegenerative disorders relevant to AD.

Chen JX, Yan SD. · Harvey Cushing Institutes of Neuroscience, North Shore-Long Island Jewish Health System, Great Neck, NY 11021, USA. · Expert Rev Neurother. · Pubmed #17997700 No free full text.

Abstract: Metabolic dysfunction is one of the early features in Alzheimer's disease (AD) affected brain. Amyloid-beta peptide (Abeta), a major peptide deposited in neuritic plaques, has been considered as an important initiating molecule in the pathogenesis of AD. However, the pathogenic role of Abeta remains to be determined. Here, we review current studies showing that progressive accumulation of Abeta occurs within the mitochondria of both transgenic mice overexpressing mutant Abeta peptide precursor protein and autopsied brains from AD patients. Interaction of Abeta with Abeta-binding alcohol dehydrogenase (ABAD), a short-chain alcohol dehydrogenase in the mitochondrial matrix, leads to mitochondrial dysfunction evidenced by increased reactive oxygen species generation, mitochondrial membrane permeability formation and caspase-3-like activity induction, and decreased activities of the Krebs cycle. These effects can be blocked by intracellular transduction of the ABAD decoy peptide. We hypothesize that Abeta-induced and mitochondria-dependent cytotoxic pathways might play an important role in AD pathogenesis and could be a potential therapeutic target.

Chen JX, Yan SD. · Harvey Cushing Institutes of Neuroscience, North Shore-Long Island Jewish Health System, Great Neck, NY 11021, USA. · J Alzheimers Dis. · Pubmed #17917162 links to  free full text

Abstract: As an important molecule in the pathogenesis of Alzheimer's disease (AD), amyloid-beta (Abeta) interferes with multiple aspects of mitochondrial function, including energy metabolism failure, production of reactive oxygen species (ROS) and permeability transition pore formation. Recent studies have demonstrated that Abeta progressively accumulates within mitochondrial matrix, providing a direct link to mitochondrial toxicity. Abeta-binding alcohol dehydrogenase (ABAD) is localized to the mitochondrial matrix and binds to mitochondrial Abeta. Interaction of ABAD with Abeta exaggerates Abeta-mediated mitochondrial and neuronal perturbation, leading to impaired synaptic function, and dysfunctional spatial learning/memory. Thus, blockade of ABAD/Abeta interaction may be a potential therapeutic strategy for AD.

Chen X, Yan SD. · Department of Neurology and Veteran Administration Medical Center, School of Medicine, Saint Louis University, St. Louis, Missouri, USA. · IUBMB Life. · Pubmed #17424907 No free full text.

Abstract: Deficits in mitochondrial function are a characteristic finding in Alzheimer's disease (AD), though the mechanism remains to be clarified. Recent studies revealed that amyloid beta peptide (Abeta) gains access into mitochondrial matrix, which was much more pronounced in both AD brain and transgenic mutant APP mice than in normal controls. Abeta progressively accumulates in mitochondria and mediates mitochondrial toxicity. Interaction of mitochondrial Abeta with mitochondrial enzymes such as amyloid beta binding alcohol dehydrogenase (ABAD) exaggerates mitochondrial stress by inhibiting the enzyme activity, releasing reactive oxygen species (ROS), and affecting glycolytic, Krebs cycle and/or the respiratory chain pathways through the accumulation of deleterious intermediate metabolites. The pathways proposed may play a key role in the pathogenesis of this devastating neurodegenerative disorder, Alzheimer's disease.

Chen X, Stern D, Yan SD. · Department of Neurology and Veteran Administration Medical Center, School of Medicine, Saint Louis University, St. Louis, MO 63106, USA. · Curr Alzheimer Res. · Pubmed #17168650 No free full text.

Abstract: Mitochondrial dysfunction has been implicated in causing metabolic abnormalities in Alzheimer's disease (AD). The searches for mitochondrial DNA variants associated with AD susceptibility have generated conflicting results. The age-related accumulation of somatic mitochondrial DNA deletion has been suggested to play a pathogenic role in the development of AD. Recent studies have demonstrated that amyloid-beta peptide (Abeta) progressively accumulates in mitochndrial matrix, as demonstrated in both transgenic mice over-expressing mutant amyloid precursor protein (APP) and autopsy brain from AD patients. Abeta-mediated mitochondrial stress was evidenced by impaired oxygen consumption and decreased respiratory chain complexes III and IV activities in brains from AD patients and AD-type transgenic mouse model. Furthermore, our studies indicated that interaction of intramitochondrial Abeta with a mitochondrial enzyme, amyloid binding alcohol dehydrogenase (ABAD), inhibits its enzyme activity, enhances generation of reactive oxygen species (ROS), impairs energy metabolism, and exaggerates Abeta-induced spatial learning/memory deficits and neuropathological changes in transgenic AD-type mouse model. Interception of ABAD-Abeta interaction may be a potential therapeutic strategy for Alzheimer's disease.

Yan SD, Xiong WC, Stern DM. · Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. · J Alzheimers Dis. · Pubmed #16873960 No free full text.

Abstract: Mitochondrial and metabolic dysfunction have been linked to Alzheimer's disease for some time. Key questions regarding this association concern the nature and mechanisms of mitochondrial dysfunction, and whether such changes in metabolic properties are pathogenic or secondary, with respect to neuronal degeneration. In terms of mitochondria and Alzheimer's, altered function could reflect intrinsic properties of this organelle, potentially due to mutations in mitochondrial DNA, or extrinsic changes secondary to signal transduction mechanisms activated in the cytosol. This review presents data relevant to these questions, and considers the implication of recent findings demonstrating the presence of amyloid-beta peptide in mitochondria, as well as intra-mitochondrial molecular targets with which it can interact. Regardless of the underlying mechanism(s), it is likely that mitochondrial dysfunction contributes to oxidant stress which is commonly observed in brains of patients with Alzheimer's and transgenic models of Alzheimer's-like pathology.

Lue LF, Yan SD, Stern DM, Walker DG. · Laboratory of Neurovascular Inflammation, Sun Health Research Institute, Sun City, AZ 85351, USA. · Curr Drug Targets CNS Neurol Disord. · Pubmed #15975028 No free full text.

Abstract: Receptor for advanced glycation endproducts (RAGE), a member of the immunoglobulin superfamily, is a multi-ligand, cell surface receptor expressed by neurons, microglia, astrocytes, cerebral endothelial cells, pericytes, and smooth muscle cells. At least three major types of the RAGE isoforms (full length, C-truncated, and N-truncated) are present in human brains as a result of alternative splicing. Differential expression of each isoform may play a regulatory role in the physiological and pathophysiological functions of RAGE. Analysis of RAGE expression in non-demented and Alzheimer's disease (AD) brains indicated that increases in RAGE protein and percentage of RAGE-expressing microglia paralleled the severity of disease. Ligands for RAGE in AD include amyloid beta peptide (Abeta), S100/calgranulins, advanced glycation endproduct-modified proteins, and amphoterin. Collective evidence from in vitro and in vivo studies supports that RAGE plays multiple roles in the pathogenesis of AD. The major features of RAGE activation in contributing to AD result from its interaction with Abeta, from the positive feedback mechanisms driven by excess amounts of Abeta, and combined with sustained elevated RAGE expression. The adverse consequences of RAGE interaction with Abeta include perturbation of neuronal properties and functions, amplification of glial inflammatory responses, elevation of oxidative stress and amyloidosis, increased Abeta influx at the blood brain barrier and vascular dysfunction, and induction of autoantibodies. In this article, we will review recent advances of RAGE and RAGE activation based on findings from cell cultures, animal models, and human brains. The potential for targeting RAGE mechanisms as therapeutic strategies for AD will be discussed.

Yan SD, Stern DM. · Departments of Pathology, Surgery, Taub Institute for Research on Alzheimer's Disease and the Ageing Brain, College of Physicians & Surgeons of Columbia University, 650 West 168th Street, Black Building Rm. 17-01, New York, NY 10032, USA. · Int J Exp Pathol. · Pubmed #15910550 No free full text.

Abstract: An important means of determining how amyloid-beta peptide (Abeta) affects cells is to identify specific macromolecular targets and assess how Abeta interaction with such targets impacts on cellular functions. On the one hand, cell surface receptors interacting with extracellular Abeta have been identified, and their engagement by amyloid peptide can trigger intracellular signaling cascades. Recent evidence has indicated a potentially significant role for deposition of intracellular Abeta in cell stress associated with amyloidosis. Thus, specific intracellular targets of Abeta might also be of interest. Our review evaluates the potential significance of Abeta interaction with a mitochondrial enzyme termed Abeta-binding alcohol dehydrogenase (ABAD), a member of the short-chain dehydrogenase-reductase family concentrated in mitochondria of neurones. Binding of Abeta to ABAD distorts the enzyme's structure, rendering it inactive with respect to its metabolic properties, and promotes mitochondrial generation of free radicals. Double transgenic mice in which increased levels of ABAD are expressed in an Abeta-rich environment, the latter provided by a mutant amyloid precursor protein transgene, demonstrate accelerated decline in spatial learning/memory and pathologic changes. These data suggest that mitochondria ABAD, ordinarily a contributor to metabolic homeostasis, has the capacity to become a pathogenic factor in an Abeta-rich environment.

Bucciarelli LG, Wendt T, Rong L, Lalla E, Hofmann MA, Goova MT, Taguchi A, Yan SF, Yan SD, Stern DM, Schmidt AM. · College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA. · Cell Mol Life Sci. · Pubmed #12222959 No free full text.

Abstract: Receptor for AGE (RAGE) is a member of the immunoglobulin superfamily that engages distinct classes of ligands. The biology of RAGE is driven by the settings in which these ligands accumulate, such as diabetes, inflammation, neurodegenerative disorders and tumors. In this review, we discuss the context of each of these classes of ligands, including advance glycation end-products, amyloid beta peptide and the family of beta sheet fibrils, S100/calgranulins and amphoterin. Implications for the role of these ligands interacting with RAGE in homeostasis and disease will be considered.

Rogers J, Lue LF, Walker DG, Yan SD, Stern D, Strohmeyer R, Kovelowski CJ. · Sun Health Research Institute, P.O. Box 1278, Sun City, AZ 85351, USA. · Ernst Schering Res Found Workshop. · Pubmed #12066415 No free full text.

This publication has no abstract.

Yan SD, Schmidt AM, Stern D. · Department of Pathology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA. · Biochem Soc Symp. · Pubmed #11447831 No free full text.

Abstract: Neurotoxicity of beta-amyloid peptide (A beta) in Alzheimer's disease (AD) is usually thought to arise from the nonspecific effects of high concentrations of A beta on vulnerable neurons, resulting in membrane destabilization and increasing intracellular calcium concentration. This review advances the hypothesis that at early stages of AD, when A beta is present in lower amounts, its ability to perturb the function of cellular targets is mediated by specific cofactors present on the cell surface and intracellularly. Receptor for advanced glycation endproducts (RAGE) is a cell-surface receptor which binds A beta and amplifies its effects on cells in the nanomolar range. The intracellular enzyme A beta-binding alcohol dehydrogenase (ABAD) is likely to engage nascent A beta formed in the endoplasmic reticulum, and to mediate cell stress from this site. The analysis of A beta interaction with RAGE and ABAD, as well as other cofactors, provides insight into new mechanisms and, potentially, identifies therapeutic targets relevant to neuronal dysfunction in AD.

Yan SD, Roher A, Chaney M, Zlokovic B, Schmidt AM, Stern D. · Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. · Biochim Biophys Acta. · Pubmed #10899440 No free full text.

Abstract: Insights into factors underlying causes of familial Alzheimer's disease (AD), such as mutant forms of beta-amyloid precursor protein and presenilins, and those conferring increased risk of sporadic AD, such as isoforms of apolipoprotein E and polymorphisms of alpha2-macroglobulin, have been rapidly emerging. However, mechanisms through which amyloid beta-peptide (Abeta), the fibrillogenic peptide most closely associated with neurotoxicity in AD, exerts its effects on cellular targets have only been more generally outlined. Late in the course of AD, when Abeta fibrils are abundant, non-specific interactions of amyloid with cellular elements are likely to induce broad cytotoxicity. However, early in AD, when concentrations of Abeta are much lower and extracellular deposits are infrequent, mechanisms underlying cellular dysfunction have not been clearly defined. The key issue in elucidating the means through which Abeta perturbs cellular properties early in AD is the possibility that protective therapy at such times may prevent cytotoxicity at a point when damage is still reversible. This brief review focusses on two cellular cofactors for Abeta-induced cellular perturbation: the cell surface immunoglobulin superfamily molecule RAGE (receptor for advanced glycation endproducts) and ABAD (Abeta binding alcohol dehydrogenase). Although final proof for the involvement of these cofactors in cellular dysfunction in AD must await the results of further in vivo experiments, their increased expression in AD brain, as well as other evidence described below, suggests the possibility of specific pathways for Abeta-induced cellular perturbation which could provide future therapeutic targets.

Yan SD, Roher A, Schmidt AM, Stern DM. · Department of Pathology, Columbia University, New York, New York, USA. · Am J Pathol. · Pubmed #10550293 links to  free full text

This publication has no abstract.

Schmidt AM, Yan SD, Wautier JL, Stern D. · Division of Surgical Science, Department of Surgery, College of Physicians & Surgeons of Columbia University, New York, NY 10032, USA. · Circ Res. · Pubmed #10082470 links to  free full text

Abstract: Receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface molecules and engages diverse ligands relevant to distinct pathological processes. One class of RAGE ligands includes glycoxidation products, termed advanced glycation end products, which occur in diabetes, at sites of oxidant stress in tissues, and in renal failure and amyloidoses. RAGE also functions as a signal transduction receptor for amyloid beta peptide, known to accumulate in Alzheimer disease in both affected brain parenchyma and cerebral vasculature. Interaction of RAGE with these ligands enhances receptor expression and initiates a positive feedback loop whereby receptor occupancy triggers increased RAGE expression, thereby perpetuating another wave of cellular activation. Sustained expression of RAGE by critical target cells, including endothelium, smooth muscle cells, mononuclear phagocytes, and neurons, in proximity to these ligands, sets the stage for chronic cellular activation and tissue damage. In a model of accelerated atherosclerosis associated with diabetes in genetically manipulated mice, blockade of cell surface RAGE by infusion of a soluble, truncated form of the receptor completely suppressed enhanced formation of vascular lesions. Amelioration of atherosclerosis in these diabetic/atherosclerotic animals by soluble RAGE occurred in the absence of changes in plasma lipids or glycemia, emphasizing the contribution of a lipid- and glycemia-independent mechanism(s) to atherogenesis, which we postulate to be interaction of RAGE with its ligands. Future studies using mice in which RAGE expression has been genetically manipulated and with selective low molecular weight RAGE inhibitors will be required to definitively assign a critical role for RAGE activation in diabetic vasculopathy. However, sustained receptor expression in a microenvironment with a plethora of ligand makes possible prolonged receptor stimulation, suggesting that interaction of cellular RAGE with its ligands could be a factor contributing to a range of important chronic disorders.

Du H, Guo L, Fang F, Chen D, Sosunov AA, McKhann GM, Yan Y, Wang C, Zhang H, Molkentin JD, Gunn-Moore FJ, Vonsattel JP, Arancio O, Chen JX, Yan SD. · Department of Surgery, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, New York 10032, USA. · Nat Med. · Pubmed #18806802 No free full text.

Abstract: Cyclophilin D (CypD, encoded by Ppif) is an integral part of the mitochondrial permeability transition pore, whose opening leads to cell death. Here we show that interaction of CypD with mitochondrial amyloid-beta protein (Abeta) potentiates mitochondrial, neuronal and synaptic stress. The CypD-deficient cortical mitochondria are resistant to Abeta- and Ca(2+)-induced mitochondrial swelling and permeability transition. Additionally, they have an increased calcium buffering capacity and generate fewer mitochondrial reactive oxygen species. Furthermore, the absence of CypD protects neurons from Abeta- and oxidative stress-induced cell death. Notably, CypD deficiency substantially improves learning and memory and synaptic function in an Alzheimer's disease mouse model and alleviates Abeta-mediated reduction of long-term potentiation. Thus, the CypD-mediated mitochondrial permeability transition pore is directly linked to the cellular and synaptic perturbations observed in the pathogenesis of Alzheimer's disease. Blockade of CypD may be a therapeutic strategy in Alzheimer's disease.

Ren Y, Xu HW, Davey F, Taylor M, Aiton J, Coote P, Fang F, Yao J, Chen D, Chen JX, Yan SD, Gunn-Moore FJ. · Schools of Biology and Medicine, University of St. Andrews, Scotland KY16 9TS. · J Biol Chem. · Pubmed #18167351 links to  free full text

Abstract: Alzheimer patients have increased levels of both the 42 amyloid-beta-peptide (Abeta) and the amyloid binding alcohol dehydrogenase (ABAD), which is an intracellular binding site for Abeta. The overexpression of Abeta and ABAD in transgenic mice has shown that the binding of Abeta to ABAD results in amplified neuronal stress and impairment of learning and memory. From a proteomic analysis of the brains from these animals, we have identified for the first time that the protein endophilin I increases in Alzheimer diseased brain. The increase in endophilin I levels in neurons is linked to an increase in the activation of the stress kinase c-Jun N-terminal kinase with the subsequent death of the neurons. We also demonstrate in living animals that the expression level of endophilin I is an indicator for the interaction of ABAD and Abeta as its expression levels return to normal if this interaction is perturbed. Therefore this identifies endophilin I as a new indicator of the progression of Alzheimer disease.

Cole AR, Noble W, van Aalten L, Plattner F, Meimaridou R, Hogan D, Taylor M, LaFrancois J, Gunn-Moore F, Verkhratsky A, Oddo S, LaFerla F, Giese KP, Dineley KT, Duff K, Richardson JC, Yan SD, Hanger DP, Allan SM, Sutherland C. · Division of Pathology and Neurosciences, University of Dundee, Ninewells Hospital, Dundee, Scotland, UK. · J Neurochem. · Pubmed #17683481 No free full text.

Abstract: Collapsin response mediator protein 2 (CRMP2) is an abundant brain-enriched protein that can regulate microtubule assembly in neurons. This function of CRMP2 is regulated by phosphorylation by glycogen synthase kinase 3 (GSK3) and cyclin-dependent kinase 5 (Cdk5). Here, using novel phosphospecific antibodies, we demonstrate that phosphorylation of CRMP2 at Ser522 (Cdk5-mediated) is increased in Alzheimer's disease (AD) brain, while CRMP2 expression and phosphorylation of the closely related isoform CRMP4 are not altered. In addition, CRMP2 phosphorylation at the Cdk5 and GSK3 sites is increased in cortex and hippocampus of the triple transgenic mouse [presenilin-1 (PS1)(M146V)KI; Thy1.2-amyloid precursor protein (APP)(swe); Thy1.2tau(P301L)] that develops AD-like plaques and tangles, as well as the double (PS1(M146V)KI; Thy1.2-APP(swe)) transgenic mouse. The hyperphosphorylation is similar in magnitude to that in human AD and is evident by 2 months of age, ahead of plaque or tangle formation. Meanwhile, there is no change in CRMP2 phosphorylation in two other transgenic mouse lines that display elevated amyloid beta peptide levels (Tg2576 and APP/amyloid beta-binding alcohol dehydrogenase). Similarly, CRMP2 phosphorylation is normal in hippocampus and cortex of Tau(P301L) mice that develop tangles but not plaques. These observations implicate hyperphosphorylation of CRMP2 as an early event in the development of AD and suggest that it can be induced by a severe APP over-expression and/or processing defect.

Yao J, Taylor M, Davey F, Ren Y, Aiton J, Coote P, Fang F, Chen JX, Yan SD, Gunn-Moore FJ. · Department of Pathology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA. · Mol Cell Neurosci. · Pubmed #17490890 No free full text.

Abstract: Alzheimer's patients have increased levels of both the 42 beta amyloid-beta-peptide (Abeta) and amyloid binding alcohol dehydrogenase (ABAD) which is an intracellular binding site for Abeta. The over-expression of Abeta and ABAD in transgenic mice has shown that the binding of Abeta to ABAD results in exaggerating neuronal stress and impairment of learning and memory. From a proteomic analysis of the brains from these animals we identified that peroxiredoxin II levels increase in Alzheimer's diseased brain. This increase in peroxiredoxin II levels protects neurons against Abeta induced toxicity. We also demonstrate, for the first time in living animals, that the expression level of peroxiredoxin II is an indicator for the interaction of ABAD and Abeta as its expression levels return to normal if this interaction is perturbed. Therefore this indicates the possibility of reversing changes observed in Alzheimer's disease and that the Abeta-ABAD interaction is a suitable drug target.

Caspersen C, Wang N, Yao J, Sosunov A, Chen X, Lustbader JW, Xu HW, Stern D, McKhann G, Yan SD. · Department of Surgery, College of Physicians & Surgeons of Columbia University, New York, New York 10032, USA. · FASEB J. · Pubmed #16210396 links to  free full text

Abstract: Although amyloid-beta peptide (Abeta) is the neurotoxic species implicated in the pathogenesis of Alzheimer's disease (AD), mechanisms through which intracellular Abeta impairs cellular properties, resulting in neuronal dysfunction, remain to be clarified. Here we demonstrate that intracellular Abeta is present in mitochondria from brains of transgenic mice with targeted neuronal overexpression of mutant human amyloid precursor protein and AD patients. Abeta progressively accumulates in mitochondria and is associated with diminished enzymatic activity of respiratory chain complexes (III and IV) and a reduction in the rate of oxygen consumption. Importantly, mitochondria-associated Abeta, principally Abeta42, was detected as early as 4 months, before extensive extracellular Abeta deposits. Our studies delineate a new means through which Abeta potentially impairs neuronal energetics, contributing to cellular dysfunction in AD.

Chaney MO, Stine WB, Kokjohn TA, Kuo YM, Esh C, Rahman A, Luehrs DC, Schmidt AM, Stern D, Yan SD, Roher AE. · Department of Surgery, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. · Biochim Biophys Acta. · Pubmed #15882940 No free full text.

Abstract: In the AD brain, there are elevated amounts of soluble and insoluble Abeta peptides which enhance the expression of membrane bound and soluble receptor for advanced glycation end products (RAGE). The binding of soluble Abeta to soluble RAGE inhibits further aggregation of Abeta peptides, while membrane bound RAGE-Abeta interactions elicit activation of the NF-kappaB transcription factor promoting sustained chronic neuroinflammation. Atomic force microscopy observations demonstrated that the N-terminal domain of RAGE, by interacting with Abeta, is a powerful inhibitor of Abeta polymerization even at prolonged periods of incubation. Hence, the potential RAGE-Abeta structural interactions were further explored utilizing a series of computational chemistry algorithms. Our modeling suggests that a soluble dimeric RAGE assembly creates a positively charged well into which the negative charges of the N-terminal domain of dimeric Abeta dock.

Fewlass DC, Noboa K, Pi-Sunyer FX, Johnston JM, Yan SD, Tezapsidis N. · Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, New York, USA. · FASEB J. · Pubmed #15576490 links to  free full text

Abstract: Abeta peptide is the major proteinateous component of the amyloid plaques found in the brains of Alzheimer's disease (AD) patients and is regarded by many as the culprit of the disorder. It is well documented that brain lipids are intricately involved in Abeta-related pathogenic pathways. An important modulator of lipid homeostasis is the pluripotent peptide leptin. Here we demonstrate leptin's ability to modify Abeta levels in vitro and in vivo. Similar to methyl-beta-cyclodextrin, leptin reduces beta-secretase activity in neuronal cells possibly by altering the lipid composition of membrane lipid rafts. This phenotype contrasts treatments with cholesterol and etomoxir, an inhibitor of carnitine-palmitoyl transferase-1. Conversely, inhibitors of acetyl CoA carboxylase and fatty acid synthase mimicked leptin's action. Leptin was also able to increase apoE-dependent Abeta uptake in vitro. Thus, leptin can modulate bidirectional Abeta kinesis, reducing its levels extracellularly. Most strikingly, chronic administration of leptin to AD-transgenic animals reduced the brain Abeta load, underlying its therapeutic potential.

Giri R, Selvaraj S, Miller CA, Hofman F, Yan SD, Stern D, Zlokovic BV, Kalra VK. · Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles 90033, USA. · Am J Physiol Cell Physiol. · Pubmed #12176746 links to  free full text

Abstract: During normal aging and amyloid beta-peptide (Abeta) disorders such as Alzheimer's disease (AD), one finds increased deposition of Abeta and activated monocytes/microglial cells in the brain. Our previous studies show that Abeta interaction with a monolayer of normal human brain microvascular endothelial cells results in increased adherence and transmigration of monocytes. Relatively little is known of the role of Abeta accumulated in the AD brain in mediating trafficking of peripheral blood monocytes (PBM) across the blood-brain barrier (BBB) and concomitant accumulation of monocytes/microglia in the AD brain. In this study, we showed that interaction of Abeta(1--40) with apical surface of monolayer of brain endothelial cells (BEC), derived either from normal or AD individuals, resulted in increased transendothelial migration of monocytic cells (HL-60 and THP-1) and PBM. However, transmigration of monocytes across the BEC monolayer cultivated in a Transwell chamber was increased 2.5-fold when Abeta was added to the basolateral side of AD compared with normal individual BEC. The Abeta-induced transmigration of monocytes was inhibited in both normal and AD-BEC by antibodies to the putative Abeta receptor, receptor for advanced glycation end products (RAGE), and to the endothelial cell junction molecule, platelet-endothelial cell adhesion molecule-1 (PECAM-1). We conclude that interaction of Abeta with the basolateral surface of AD-BEC induces cellular signaling, promoting transmigration of monocytes from the apical to basolateral direction. We suggest that Abeta in the AD brain parenchyma or cerebrovasculature initiates cellular signaling that induces PBM to transmigrate across the BBB and accumulate in the brain.

Lue LF, Walker DG, Brachova L, Beach TG, Rogers J, Schmidt AM, Stern DM, Yan SD. · The Roberts Alzheimer's Disease Center, Sun Health Research Institute, Sun City, Arizona 85372, USA. · Exp Neurol. · Pubmed #11520119 No free full text.

Abstract: Receptor-mediated interactions with amyloid beta-peptide (Abeta) could be important in the evolution of the inflammatory processes and cellular dysfunction that are prominent in Alzheimer's disease (AD) pathology. One candidate receptor is the receptor for advanced glycation endproducts (RAGE), which can bind Abeta and transduce signals leading to cellular activation. Data are presented showing a potential mechanism for Abeta activation of microglia that could be mediated by RAGE and macrophage colony-stimulating factor (M-CSF). Using brain tissue from AD and nondemented (ND) individuals, RAGE expression was shown to be present on microglia and neurons of the hippocampus, entorhinal cortex, and superior frontal gyrus. The presence of increased numbers of RAGE-immunoreactive microglia in AD led us to further analyze RAGE-related properties of these cells cultured from AD and ND brains. Direct addition of Abeta(1-42) to the microglia increased their expression of M-CSF. This effect was significantly greater in microglia derived from AD brains compared to those from ND brains. Increased M-CSF secretion was also demonstrated using a cell culture model of plaques whereby microglia were cultured in wells containing focal deposits of immobilized Abeta(1-42). In each case, the Abeta stimulation of M-CSF secretion was significantly blocked by treatment of cultures with anti-RAGE F(ab')2. Treatment of microglia with anti-RAGE F(ab')2 also inhibited the chemotactic response of microglia toward Abeta(1-42). Finally, incubation of microglia with M-CSF and Abeta increased expression of RAGE mRNA. These microglia also expressed M-CSF receptor mRNA. These data suggest a positive feedback loop in which Abeta-RAGE-mediated microglial activation enhances expression of M-CSF and RAGE, possibly initiating an ascending spiral of cellular activation.

Lue LF, Rydel R, Brigham EF, Yang LB, Hampel H, Murphy GM, Brachova L, Yan SD, Walker DG, Shen Y, Rogers J. · Sun Health Research Institute, Sun City, Arizona 85372, USA. · Glia. · Pubmed #11424194 No free full text.

Abstract: We have previously developed and characterized isolated microglia and astrocyte cultures from rapid (<4 h) brain autopsies of Alzheimer's disease (AD) and nondemented elderly control (ND) patients. In the present study, we evaluate the inflammatory repertoire of AD and ND microglia cultured from white matter (corpus callosum) and gray matter (superior frontal gyrus) with respect to three major proinflammatory cytokines, three chemokines, a classical pathway complement component, a scavenger cell growth factor, and a reactive nitrogen intermediate. Significant, dose-dependent increases in the production of pro-interleukin-1beta (pro-IL-1beta), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory peptide-1alpha (MIP-1alpha), IL-8, and macrophage colony-stimulating factor (M-CSF) were observed after exposure to pre-aggregated amyloid beta peptide (1-42) (Abeta1-42). Across constitutive and Abeta-stimulated conditions, secretion of complement component C1q, a reactive nitrogen intermediate, and M-CSF was significantly higher in AD compared with ND microglia. Taken together with previous in situ hybridization findings, these results demonstrate unequivocally that elderly human microglia provide a brain endogenous source for a wide range of inflammatory mediators.