Philippe Marambaud, PhD Director

Dr. Philippe Marambaud's research focuses on the molecular basis of neuronal degeneration in Alzheimer's disease (AD). His laboratory studies the early biochemical changes leading to the formation of two classic lesions of the AD brain, the senile plaques and the neurofibrillary tangles. The scientists in his lab have developed genetic, molecular and cell-biology methods for the purification and analysis of the core components of these lesions, the amyloid-beta peptides and the hyperphosphorylated tau. They are also studying the central role of presenilins and presenilin-interacting proteins in amyloid precursor protein (APP) and cadherin processing and signaling, and the mechanisms by which AD-linked presenilin mutations interfere with these pathways.

 Biochemical and cell biology studies of human brain tissues are complemented by cell culture systems and protein analysis. Dr. Marambaud's research also involves expression in cultured cells of APP and tau constructs and analysis of transgenic laboratory models of amyloid accumulation.

The team has recently identified CALHM1, a novel risk gene for late-onset AD. Dr. Marambaud is principal investigator of grants from the Alzheimer's Association, the Institute for the Study of Aging, and NCCAM at the National Institutes of Health.

Lab Members

Name: Hemachander Capiralla, PhD
Position: Postdoctoral Research Fellow
Research: Molecular genetics of Alzheimer's disease.
E-mail: hcapiral@nshs.edu

Name: Julien Chapuis, PhD
Position: Postdoctoral Research Fellow
Research: Molecular genetics of Alzheimer's disease.
E-mail: Jchapuis@nshs.edu

Name: Ute Dreses-Werringloer, PhD
Position: Research Scientist
Research: Molecular genetics of Alzheimer's disease.
E-mail: udreses@nshs.edu

Name: Valerie Vingtdeux, PhD
Position: Research Scientist
Research: Molecular genetics of Alzheimer's
E-mail: vdidier@nshs.edu

Name:Haitian Zhao, MSc
Position: Research Assistant
Research: Molecular Genetics of Alzheimer's
E-mail: hzhao@nshs.edu

Name: Pallavi Kozarekar, MSc
Position: Research Assistant
Research: Molecular Genetics of Alzheimer's
E-mail: PKozarekar@nshs.edu

Publications

Marambaud P, Wilk S, Checler F. Protein kinase A phosphorylation of the proteasome: a contribution to the alpha-secretase pathway in human cells. J Neurochem 1996 Dec; 67(6):2616-9.

Marambaud P, Chevallier N, Barelli H, Wilk S, Checler F. Proteasome contributes to the alpha-secretase pathway of amyloid precursor protein in human cells. J Neurochem 1997 Feb; 68(2):698-703.

Chevallier N, Vizzavona J, Marambaud P, Baur CP, Spillantini M, Fulcrand P, Martinez J, Goedert M, Vincent JP, Checler F. Cathepsin D displays in vitro beta-secretase-like specificity. Brain Res 1997 Mar 7; 750(1-2):11-9.

Marambaud P, Rieunier F, Wilk S, Martinez J, Checler F. Contribution of the proteasome to the alpha-secretase pathway in Alzheimer's disease. Adv Exp Med Biol 1997; 421:267-72.

Barelli H, Lebeau A, Vizzavona J, Delaere P, Chevallier N, Drouot C, Marambaud P, Ancolio K, Buxbaum JD, Khorkova O, Heroux J, Sahasrabudhe S, Martinez J, Warter JM, Mohr M, Checler F. Characterization of new polyclonal antibodies specific for 40 and 42 amino acid-long amyloid beta peptides: their use to examine the cell biology of presenilins and the immunohistochemistry of sporadic Alzheimer's disease and cerebral amyloid angiopathy cases. Mol Med 1997 Oct;3(10):695-707.

Ancolio K, Marambaud P, Dauch P, Checler F. Alpha-secretase-derived product of beta-amyloid precursor protein is decreased by presenilin 1 mutations linked to familial Alzheimer's disease. J Neurochem 1997 Dec; 69(6):2494-9.

Marambaud P, Lopez-Perez E, Wilk S, Checler F. Constitutive and protein kinase C-regulated secretory cleavage of Alzheimer's beta-amyloid precursor protein: different control of early and late events by the proteasome. J Neurochem 1997 Dec; 69(6):2500-5.

Marambaud P, Ancolio K, Lopez-Perez E, Checler F. Proteasome inhibitors prevent the degradation of familial Alzheimer's disease-linked presenilin 1 and potentiate A-beta 42 recovery from human cells. Mol Med 1998 Mar; 4(3):147-57.

Marambaud P, Chevallier N, Lopez-Perez E, Drouot C, Vizzanova J, Fulcrand P, Martinez J, Wilk S, Checler F. Strategies for identification of secretases implicated in Alzheimer's disease. Ann Biol Clin (Paris) 1998 May-Jun; 56(3):277-84.

Marambaud P, Alves da Costa C, Ancolio K, Checler F. Alzheimer's disease-linked mutation of presenilin 2 (N141I-PS2) drastically lowers APPalpha secretion: control by the proteasome. Biochem Biophys Res Commun 1998 Nov 9;252(1):134-8.

Marambaud P, Chevallier N, Ancolio K, Checler F. Post-transcriptional contribution of a cAMP-dependent pathway to the formation of alpha- and beta/gamma-secretases-derived products of beta APP maturation in human cells expressing wild-type and Swedish mutated beta APP. Mol Med 1998 Nov; 4(11):715-23.

Marambaud P, Ancolio K, Alves da Costa C, Checler F. Effect of protein kinase A inhibitors on the production of Abeta40 and Abeta42 by human cells expressing normal and Alzheimer's disease-linked mutated betaAPP and presenilin 1. Br J Pharmacol 1999 Mar; 126(5):1186-90.

Georgakopoulos A, Marambaud P, Efthimiopoulos S, Shioi J, Cui W, Li D, Schutte M, Gordon R, Mehta P, Friedrich Jr VL, Robakis NK. Presenilin 1 is recruited to cell-cell contacts, forms complexes with the cadherin/catenin adhesion system and regulates cell-cell adhesion. Mol Cell. 1999 Dec;4(6):893-902.

Georgakopoulos A, Marambaud P, Friedrich VL Jr, Shioi J, Efthimiopoulos S, Robakis NK. Presenilin-1: a component of synaptic and endothelial adherens junctions. Ann N Y Acad Sci 2000;920:209-14.

Checler F, Alves da Costa C, Ancolio K, Lopez-Perez Elvira, Marambaud P. Role of the proteasome in Alzheimer’s Disease. Biochim Biophys Acta. 2000 Jul 26;1502(1):133-8.

Marambaud P, Baki L, Efthimiopoulos S, Georgakopoulos A, Wen P, Cui W, Ozawa M, Friedrich Jr VL, Robakis NK. Presenilin-1 binds cytoplasmic epithelial cadherin, inhibits epithelial cadherin/p120 association, and regulates stability and function of the cadherin adhesion complex. Proc Natl Acad Sci U S A. 2001 Feb 27; 98(5):2381-6.

Marambaud P, Shioi J, Serban G, Georgakopoulos A, Sarner S, Nagy V, Baki L, Wen P, Efthimiopoulos S, Shao Z, Wisniewski T, Robakis NK. A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J 2002 Apr 15; 21(8):1948-56.

Marambaud P, Wen PH, Dutt A, Shioi J, Takashima A, Siman R, Robakis NK. A CBP-binding transcriptional repressor produced by the PS1/e-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Cell 2003, 114, 635-645. (commentary by Rao and Finkbeiner, Cell 2003, 114: 533-535; and by Fortini M., Nature 2003, 425: 565-566).

Petit A, Pasini A, Alves da Costa C, Ayral E, Hernandez JF, Dumanchin-Njock C, Phiel CJ, Marambaud P, Wilk S, Farzan M, Fulcrand P, Martinez J, Andrau D, Checler F. JLK isocoumarin inhibitors: selective γ-secretase inhibitors that do not interfere with Notch pathway, in vitro and in vivo. J Neurosci Res 2003, 74, 370-377.

Marambaud P and Robakis NK. Genetic and Molecular Aspects of Alzheimer’s disease Shed Light on New Mechanisms of Transcriptional Regulation. Genes, Brain and Behavior 2005, 4, 134-146.

d'Abramo C, Massone S, Zingg JM, Pizzuti A, Marambaud P, Dalla Piccola B, Azzi A, Marinari UM, Pronzato A, Ricciarelli R. Role of peroxisome proliferator-activated receptor gamma in amyloid precursor protein processing and amyloid beta-mediated cell death. Biochem J 2005, 391: 693-8.

Frederic C, Cristine Ada C, Erwan A, David A, Cecile D, Michael F, Jean-Fran Ois H, Martinez J, Solveig LJ, Marambaud P, Andrea P, Agnes P, Christopher P, Philippe R, Peter SG, Sherwin W. JLK Inhibitors: Isocoumarin Compounds as Putative Probes to Selectively Target the gamma-Secretase Pathway.
Curr Alzheimer Res 2005, 2:327-334.

Marambaud P, Zhao H, Davies P. Resveratrol promotes clearance of Alzheimer's disease amyloid-beta peptides. J Biol Chem. 2005, 280: 37377-82.

Agiostratidou G, Muros RM, Shioi J, Marambaud P, Robakis NK. The cytoplasmic sequence of E-cadherin promotes non-amyloidogenic degradation of Abeta precursors. J Neurochem 2006, 96(4):1182-8.

Chen F, Hasegawa H, Schmitt-Ulms G, Kawarai T, Bohm C, Katayama T, Gu Y, Sanjo N, Glista M, Rogaeva E, Wakutani Y, Pardossi-Piquard R, Ruan X, Tandon A, Checler F, Marambaud P, Hansen K, Westaway D, St George-Hyslop P, Fraser P. TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity. Nature. 2006, 440 (7088): 1208-12.

Vingtdeux V, Hamdane M, Begard S, Loyens A, Delacourte A, Beauvillain JC, Buee L, Marambaud P, Sergeant N. Intracellular pH regulates amyloid precursor protein intracellular domain accumulation. Neurobiol Dis. 2007, 25(3): 686-96.

Zhao H, Dreses-Werringloer U, Davies P, Marambaud P. Amyloid-beta peptide degradation in cell cultures by mycoplasma contaminants. BMC Res Notes 2008 Jun 30;1:38.

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. CNI-1493 inhibits Abeta production, plaque formation, and cognitive deterioration in an animal model of Alzheimer's disease. J Exp Med 2008 Jul 7;205(7):1593-9.

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. A polymorphism in CALHM1 influences Ca2+ homeostasis, Abeta levels, and Alzheimer's disease risk. Cell 2008 Jun 27;133(7):1149-61.

Campagne F, Lambert JC, Dreses-Werringloer U, Vingtdeux V, Lendon C, Campion D, Amouyel P, Lee AT, Gregersen PK, Davies P, Marambaud P. CALHM1 Association with Alzheimer’s Disease Risk. Cell 2008 Dec 12; 135(6):994-6.

Lambert JC, Campagne F, Marambaud P. CALHM1, a novel gene to blame in Alzheimer disease. Med Sci (Paris) 2008 Nov;24(11):923-924.

Vingtdeux V, Dreses-Werringloer U, Zhao H, Davies P, Marambaud P. Therapeutic potential of resveratrol in Alzheimer's disease. BMC Neurosci 2008 Dec 3; 9 Suppl 2:S6.

Koppel J, Bradshaw H, Goldberg TE, Khalili H, Marambaud P, Walker MJ, Pazos M, Gordon ML, Christen E, Davies P. Endocannabinoids in Alzheimer's disease and their impact on normative cognitive performance: a case-control and cohort study. Lipids Health Dis 2009 Jan 14;8:2.

Marambaud P, Dreses-Werringloer U, Vingtdeux V. Calcium signaling in neurodegeneration. Mol Neurodegener. 2009 May 6;4:20.

Vingtdeux V, Giliberto L, Zhao H, Chandakkar P, Wu Q, Simon JE, Janle EM, Lobo J, Ferruzzi MG, Davies P, Marambaud P. AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-beta
peptide metabolism. J Biol Chem. 2010 Mar 19;285(12):9100-13.