Alzheimer Disease: Marambaud P

Vingtdeux V, Dreses-Werringloer U, Zhao H, Davies P, Marambaud P. · Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, North Shore-LIJ, Manhasset, NY 11030, USA. · BMC Neurosci. · Pubmed #19090994 links to  free full text

Abstract: Several epidemiological studies indicate that moderate consumption of red wine is associated with a lower incidence of dementia and Alzheimer's disease. Red wine is enriched in antioxidant polyphenols with potential neuroprotective activities. Despite scepticism concerning the bioavailability of these polyphenols, in vivo data have clearly demonstrated the neuroprotective properties of the naturally occurring polyphenol resveratrol in rodent models for stress and diseases. Furthermore, recent work in cell cultures and animal models has shed light on the molecular mechanisms potentially involved in the beneficial effects of resveratrol intake against the neurodegenerative process in Alzheimer's disease.

Marambaud P, Robakis NK. · Department of Psychiatry and Fishberg Research Center for Neurobiology, Mount Sinai School of Medicine, New York, New York 10029, USA. · Genes Brain Behav. · Pubmed #15810902 No free full text.

Abstract: Rapid advances made in biological research aimed at understanding the molecular basis of the pathogenesis of Alzheimer's disease have led to the characterization of a novel catalytic activity termed gamma-secretase. First described for its beta-amyloid-producing function, gamma-secretase is now actively studied for its role in a novel signal transduction paradigm, which implicates cell-surface receptor proteolysis and direct surface-to-nucleus signal transduction. gamma-Secretase targets numerous type I protein receptors involved in diverse functions ranging from normal development to neurodegeneration. In this Review we discuss how the study of the genetic and molecular aspects of Alzheimer's disease has revealed a dual role of gamma-secretase in transcriptional regulation and in the pathogenesis of familial Alzheimer's disease.

Georgakopoulos A, Marambaud P, Friedrich VL, Shioi J, Efthimiopoulos S, Robakis NK. · Department of Psychiatry and Fishberg Research Center for Neurobiology, Mount Sinai School of Medicine, New York, New York 10029, USA. · Ann N Y Acad Sci. · Pubmed #11193152 No free full text.

This publication has no abstract.

Checler F, da Costa CA, Ancolio K, Chevallier N, Lopez-Perez E, Marambaud P. · Institut de Pharmacologie Moléculaire et Cellulaire, UPR411 du CNRS, Sophia Antipolis, Valbonne, France. · Biochim Biophys Acta. · Pubmed #10899438 No free full text.

Abstract: The proteasome is a multicatalytic complex involved in the degradation of polyubiquitinated proteins. Here we review the clues of a possible involvement of the proteasome in Alzheimer's disease neuropathology. Thus, we discuss the fact that the proteasome modulates the intracellular concentrations of presenilins 1 and 2. These two proteins, when mutated, appear responsible for most of early onset forms of Alzheimer's disease and this is thought to be due to the exacerbation of the pathogenic pathway of the maturation of the beta-amyloid precursor protein. Controlling presenilins concentrations could have drastic repercussions on cell physiology as suggested by the fact that proteasome inhibitors drastically potentiate the 'normal' or 'pathogenic' presenilins phenotype related with betaAPP processing. The possibility of considering the proteasome as a potential target for therapeutic intervention in Alzheimer's disease is discussed.

Koppel J, Bradshaw H, Goldberg TE, Khalili H, Marambaud P, Walker MJ, Pazos M, Gordon ML, Christen E, Davies P. · The Litwin-Zucker Research Center for the Study of Alzheimer's Disease and Memory Disorders, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA. · Lipids Health Dis. · Pubmed #19144193 links to  free full text

Abstract: BACKGROUND: Neuropathological, animal, and cell culture studies point to a role for the body's own endogenous cannabinoids (eCBs) system in Alzheimer's disease (AD) pathology and treatment. To date, no published studies have investigated the potential utility of circulating eCBs as diagnostic biomarkers for AD or the impact of central eCBs on cognition. RESULTS: In comparison with healthy controls, there were no significant differences in measured eCB concentrations in plasma samples from patients with AD. Detectable eCBs in cerebrospinal fluid (CSF) had no relationship to cognitive performance in healthy controls at risk for AD. In pooled plasma samples, an inverse correlation was observed between plasma levels of the eCB 2-AG (2-arachidonoylglycerol) and TNF-alpha (r = -0.41, p < 0.02). CONCLUSION: These results suggest that circulating endocannabinoids do not have utility as diagnostic biomarkers for AD and do not have a robust correlation with cognitive performance. Circulating levels of 2-AG may downregulate TNF-alpha production.

Zhao H, Dreses-Werringloer U, Davies P, Marambaud P. · Litwin-Zucker Research Center for the Study of Alzheimer Disease, The Feinstein Institute for Medical Research, North Shore-LIJ, Manhasset, NY, USA. · BMC Res Notes. · Pubmed #18710491 links to  free full text

Abstract: ABSTRACT: BACKGROUND: Cell cultures have become an indispensable tool in Alzheimer's disease research for studying amyloid-beta (Abeta) metabolism. It is estimated that up to 35% of cell cultures in current use are infected with various mycoplasma species. In contrast with common bacterial and fungal infections, contaminations of cell cultures with mycoplasmas represent a challenging issue in terms of detectability and prevention. Mycoplasmas are the smallest and simplest self-replicating bacteria and the consequences of an infection for the host cells are variable, ranging from no apparent effect to induction of apoptosis. FINDINGS: Here we present evidence that mycoplasmas from a cell culture contamination are able to efficiently and rapidly degrade extracellular Abeta. As a result, we observed no accumulation of Abeta in the conditioned medium of mycoplasma-positive cells stably transfected with the amyloid-beta precursor protein (APP). Importantly, eradication of the mycoplasma contaminant - identified as M. hyorhinis - by treatments with a quinolone-based antibiotic, restored extracellular Abeta accumulation in the APP-transfected cells. CONCLUSION: These data show that mycoplasmas degrade Abeta and thus may represent a significant source of variability when comparing extracellular Abeta levels in different cell lines. On the basis of these results, we recommend assessment of mycoplasma contaminations prior to extracellular Abeta level measurements in cultured cells.

Dreses-Werringloer U, Lambert JC, Vingtdeux V, Zhao H, Vais H, Siebert A, Jain A, Koppel J, Rovelet-Lecrux A, Hannequin D, Pasquier F, Galimberti D, Scarpini E, Mann D, Lendon C, Campion D, Amouyel P, Davies P, Foskett JK, Campagne F, Marambaud P. · Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, North Shore-LIJ, Manhasset, NY 11030, USA. · Cell. · Pubmed #18585350 links to  free full text

Abstract: Alzheimer's disease (AD) is a genetically heterogeneous disorder characterized by early hippocampal atrophy and cerebral amyloid-beta (Abeta) peptide deposition. Using TissueInfo to screen for genes preferentially expressed in the hippocampus and located in AD linkage regions, we identified a gene on 10q24.33 that we call CALHM1. We show that CALHM1 encodes a multipass transmembrane glycoprotein that controls cytosolic Ca(2+) concentrations and Abeta levels. CALHM1 homomultimerizes, shares strong sequence similarities with the selectivity filter of the NMDA receptor, and generates a large Ca(2+) conductance across the plasma membrane. Importantly, we determined that the CALHM1 P86L polymorphism (rs2986017) is significantly associated with AD in independent case-control studies of 3404 participants (allele-specific OR = 1.44, p = 2 x 10(-10)). We further found that the P86L polymorphism increases Abeta levels by interfering with CALHM1-mediated Ca(2+) permeability. We propose that CALHM1 encodes an essential component of a previously uncharacterized cerebral Ca(2+) channel that controls Abeta levels and susceptibility to late-onset AD.

Bacher M, Dodel R, Aljabari B, Keyvani K, Marambaud P, Kayed R, Glabe C, Goertz N, Hoppmann A, Sachser N, Klotsche J, Schnell S, Lewejohann L, Al-Abed Y. · Department of Neurology, Philipps-University Marburg, 35039 Marburg, Germany. · J Exp Med. · Pubmed #18573905 links to  free full text

Abstract: Alzheimer's disease (AD) is characterized by neuronal atrophy caused by soluble amyloid beta protein (Abeta) peptide "oligomers" and a microglial-mediated inflammatory response elicited by extensive amyloid deposition in the brain. We show that CNI-1493, a tetravalent guanylhydrazone with established antiinflammatory properties, interferes with Abeta assembly and protects neuronal cells from the toxic effect of soluble Abeta oligomers. Administration of CNI-1493 to TgCRND8 mice overexpressing human amyloid precursor protein (APP) for a treatment period of 8 wk significantly reduced Abeta deposition. CNI-1493 treatment resulted in 70% reduction of amyloid plaque area in the cortex and 87% reduction in the hippocampus of these animals. Administration of CNI-1493 significantly improved memory performance in a cognition task compared with vehicle-treated mice. In vitro analysis of CNI-1493 on APP processing in an APP-overexpressing cell line revealed a significant dose-dependent decrease of total Abeta accumulation. This study indicates that the antiinflammatory agent CNI-1493 can ameliorate the pathophysiology and cognitive defects in a murine model of AD.

Vingtdeux V, Hamdane M, Bégard S, Loyens A, Delacourte A, Beauvillain JC, Buée L, Marambaud P, Sergeant N. · INSERM U815, Centre Jean-Pierre Aubert, Neurodegenerative Disorders and Neuronal Death, 1, Place de Verdun, F-59045 Lille, France. · Neurobiol Dis. · Pubmed #17207630 No free full text.

Abstract: The amyloid precursor protein (APP) metabolism is central to pathogenesis of Alzheimer's disease (AD). Parenchymal amyloid deposits, a neuropathological hallmark of AD, are composed of amyloid-beta peptides (Abeta). Abeta derives from the amyloid precursor protein (APP) by sequential cleavages by beta- and gamma-secretases. Gamma-secretase cleavage releases the APP intracellular domain (AICD), suggested to mediate a nuclear signaling. Physiologically, AICD is seldom detected and thus supposed to be rapidly degraded. The mechanisms responsible of its degradation remain unknown. We used a pharmacological approach and showed that several alkalizing drugs induce the accumulation of AICD in neuroblastoma SY5Y cell lines stably expressing APP constructs. Moreover, alkalizing drugs induce AICD accumulation in naive SY5Y, HEK and COS cells. This accumulation is not mediated by the proteasome or metallopeptidases and is not the result of an increased gamma-secretase activity since the gamma-secretase cleavage of Notch1 and N-Cadherin is not affected by alkalizing drug treatments. Altogether, our data demonstrate for the first time that alkalizing drugs induce the accumulation of AICD, a mechanism likely mediated by the endosome/lysosome pathway.

Marambaud P, Zhao H, Davies P. · Litwin-Zucker Research Center for the Study of Alzheimer's Disease and Memory Disorders, North Shore-Long Island Jewish Institute for Medical Research, Manhasset, NY 11030, USA. · J Biol Chem. · Pubmed #16162502 links to  free full text

Abstract: Several epidemiological studies indicate that moderate consumption of wine is associated with a lower incidence of Alzheimer's disease. Wine is enriched in antioxidant compounds with potential neuroprotective activities. However, the exact molecular mechanisms involved in the beneficial effects of wine intake on the neurodegenerative process in Alzheimer's disease brain remain to be clearly defined. Here we show that resveratrol (trans-3,4',5-trihydroxystilbene), a naturally occurring polyphenol mainly found in grapes and red wine, markedly lowers the levels of secreted and intracellular amyloid-beta (Abeta) peptides produced from different cell lines. Resveratrol does not inhibit Abeta production, because it has no effect on the Abeta-producing enzymes beta- and gamma-secretases, but promotes instead intracellular degradation of Abeta via a mechanism that involves the proteasome. Indeed, the resveratrol-induced decrease of Abeta could be prevented by several selective proteasome inhibitors and by siRNA-directed silencing of the proteasome subunit beta5. These findings demonstrate a proteasome-dependent anti-amyloidogenic activity of resveratrol and suggest that this natural compound has a therapeutic potential in Alzheimer's disease.

d'Abramo C, Massone S, Zingg JM, Pizzuti A, Marambaud P, Dalla Piccola B, Azzi A, Marinari UM, Pronzato MA, Ricciarelli R. · Department of Experimental Medicine, University of Genoa, 16132 Genoa, Italy. · Biochem J. · Pubmed #15946122 links to  free full text

Abstract: Recent data indicate that PPARgamma (peroxisome proliferator-activated receptor gamma) could be involved in the modulation of the amyloid cascade causing Alzheimer's disease. In the present study we show that PPARgamma overexpression in cultured cells dramatically reduced Abeta (amyloid-beta) secretion, affecting the expression of the APP (Abeta precursor protein) at a post-transcriptional level. APP down-regulation did not involve the pathway of the secretases and correlated with a significant induction of APP ubiquitination. Additionally, we demonstrate that PPARgamma was able to protect the cells from H(2)O(2)-induced necrosis by decreasing Abeta secretion. Taken together, our results indicate a novel mechanism at the basis of the neuroprotection shown by PPARgamma agonists and an additional pathogenic role for Abeta accumulation.

Baki L, Marambaud P, Efthimiopoulos S, Georgakopoulos A, Wen P, Cui W, Shioi J, Koo E, Ozawa M, Friedrich VL, Robakis NK. · Department of Psychiatry, Fishberg Research Center for Neurobiology, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY 10029, USA. · Proc Natl Acad Sci U S A. · Pubmed #11226248 links to  free full text

Abstract: Here we show that presenilin-1 (PS1), a protein involved in Alzheimer's disease, binds directly to epithelial cadherin (E-cadherin). This binding is mediated by the large cytoplasmic loop of PS1 and requires the membrane-proximal cytoplasmic sequence 604-615 of mature E-cadherin. This sequence is also required for E-cadherin binding of protein p120, a known regulator of cadherin-mediated cell adhesion. Using wild-type and PS1 knockout cells, we found that increasing PS1 levels suppresses p120/E-cadherin binding, and increasing p120 levels suppresses PS1/E-cadherin binding. Thus PS1 and p120 bind to and mutually compete for cellular E-cadherin. Furthermore, PS1 stimulates E-cadherin binding to beta- and gamma-catenin, promotes cytoskeletal association of the cadherin/catenin complexes, and increases Ca(2+)-dependent cell-cell aggregation. Remarkably, PS1 familial Alzheimer disease mutant DeltaE9 increased neither the levels of cadherin/catenin complexes nor cell aggregation, suggesting that this familial Alzheimer disease mutation interferes with cadherin-based cell-cell adhesion. These data identify PS1 as an E-cadherin-binding protein and a regulator of E-cadherin function in vivo.

Marambaud P, Ancolio K, Alves da Costa C, Checler F. · Institut de Pharmacologie Moléculaire et Cellulaire du CNRS, UPR411, Valbonne, France. · Br J Pharmacol. · Pubmed #10205007 links to  free full text

Abstract: 1. We previously established that the formation of both alpha- and beta/gamma-secretase-derived products generated by human embryonic kidney 293 cells (HEK293) expressing either wild type or mutant betaAPP could be stimulated by agonists of the cyclic AMP/protein kinase A pathways. This cyclic AMP-dependent effect modulates post-translational events since it is not prevented by actinomycin D or cycloheximide. 2. We show here that two protein kinase A inhibitors, H89 and PKI, both trigger dose-dependent inhibition of the basal constitutive production of Abeta40 and Abeta42 by HEK293 cells expressing wild type betaAPP751. 3. H89 also potently inhibits the total Abeta produced by the neocortical neuronal cell line TSM1. 4. These two inhibitors also drastically reduce the recovery of Abeta40 and Abeta42 produced by HEK293 cells expressing the Swedish (Sw) betaAPP and M146V-presenilin 1 (PS1) mutations responsible for cases of the early-onset forms of Familial Alzheimer's disease (FAD). 5. By contrast, H89 and PKI do not significantly affect the recovery of the physiological alpha-secretase-derived fragment APPalpha. 6. Our study indicates that protein kinase A inhibitors selectively lower the formation of Abeta40 and Abeta42 in human cells expressing normal and mutant betaAPP and PS1 without affecting the physiological alpha-secretase pathway in these cells. Selective inhibitors of protein kinase A may be of therapeutic value in both sporadic and Familial Alzheimer's disease, since they may decrease the production of Abeta that is thought to be responsible for the neurodegenerative process.

Lambert JC, Campagne F, Marambaud P. · No affiliation provided · Med Sci (Paris). · Pubmed #19038093 No free full text.

This publication has no abstract.