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The Feinstein Institute for Medical Research

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Philippe Marambaud, PhD

Associate Investigator, The Feinstein Institute for Medical Research

Director, Laboratory of Memory Disorders, Litwin-Zucker Research Center for the Study of Alzheimer’s Disease

Phone: (516) 562-0425
Email: pmaramba@nshs.edu

About the Investigator

For the past 18 years, the major goal of Dr. Marambaud’s research has been to elucidate the molecular basis of neuronal degeneration in Alzheimer’s disease. Dr. Marambaud is currently an associate investigator at the Litwin-Zucker Research Center at the Feinstein Institute for Medical Research, North Shore-LIJ Health System, where he directs the Laboratory of Memory Disorders.

The major accomplishments of his research include the discovery that the presenilin/gamma-secretase complex (a drug target for Alzheimer’s disease) is involved in the proteolysis and function of the adhesion proteins, E- and N-cadherins. This work, which was conducted in Dr. Nik Robakis’ laboratory (Mount Sinai School of Medicine, NY), revealed important new aspects of cadherin and presenilin biology and increased our understanding of the relevance of these two proteins for Alzheimer’s disease pathogenesis.

In collaboration with Dr. Peter Davies, Dr. Marambaud’s research also led to the discovery of the key role played by the Ser/Thr protein kinase AMPK in tau phosphorylation and in the anti-amyloidogenic properties of the natural polyphenol resveratrol. The latter work significantly contributed to motivate the current clinical trials aimed at assessing the beneficial effects of resveratrol intake against Alzheimer’s disease.

Another major accomplishment of Dr. Marambaud’s team is the discovery in 2008 of the channel protein CALHM1, a work conducted in collaboration with the bioinformatics lab of Dr. Fabien Campagne at the Weill Medical College of Cornell University, NY.

Research Focus

Dr. Philippe Marambaud’s research focuses on the molecular basis of neuronal degeneration in Alzheimer’s disease and other dementias. His laboratory studies the early biochemical changes leading to the formation of two classic lesions of the Alzheimer’s disease 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 hyperphosphorylated tau proteins. They also study the central role of presenilins and presenilin-interacting proteins in amyloid precursor protein (APP) and cadherin processing and signaling, and the mechanisms by which Alzheimer’s disease-linked presenilin mutations interfere with these pathways.

Biochemical and cell biology studies of human brain tissues are complemented by cell culture systems and protein analyses. The research also involves expression in cultured cells of APP and tau constructs and analysis of transgenic laboratory models of amyloid and tau pathologies.

The current research is directed towards the study of the channel protein CALHM1 and the Ser/Thr protein kinase AMPK in mouse physiology and in the pathogenesis of Alzheimer’s disease and other dementias.

Lab Members

Valerie Vingtdeux, PhD
Research Scientist
Email: vdidier@nshs.edu

Haitian Zhao, MSc
Research Assistant
Email: hzhao@nshs.edu

Pallavi Kozarekar, MSc
Research Assistant
Email: pkozarekar@nshs.edu

Leslie R Adrien, MSc
Research Assistant
Email: ladrien@nshs.edu

Education

University of Nice-Sophia Antipolis, France
Degree: MSc
1994
Field of Study: Pharmacology, Cell & Molecular Biology

University of Nice-Sophia Antipolis, France
Degree: PhD
1998
Field of Study: Pharmacology, Cell & Molecular Biology

Awards & Honors

1999 Scholarship award of the ARC Association
2000 Philippe Foundation award, New York
2007 KeySpan Fellowship Award

Publications
  1. 1. 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; 21(8):1948-56.
  2. Marambaud P, Wen PH, Dutt A, Shioi J, Takashima A, Siman R, Robakis NK. “A CBP-binding transcriptional repressor produced by the PS1/gamma-cleavage of N-cadherin is inhibited by PS1 FAD mutations.” Cell 2003; 114, 635-645.
  3. Marambaud P, Zhao H, Davies P. “Resveratrol promotes clearance of Alzheimer’s disease amyloid-beta peptides.” J Biol Chem 2005, 280: 37377-82.
  4. 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; 133(7):1149-61.
  5. 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;285(12):9100-13.
  6. Vingtdeux V, Davies P, Dickson DW, Marambaud P. “AMPK is abnormally activated in tangle- and pre-tangle-bearing neurons in Alzheimer’s disease and other tauopathies.” Acta Neuropathol 2011; 121(3):337-49.
  7. Koppel J, Campagne F, Vingtdeux V, Dreses-Werringloer U, Ewers M, Rujescu D, Hampel H, Gordon ML, Christen E, Chapuis J, Greenwald BS, Davies P, Marambaud P. “CALHM1 P86L polymorphism modulates CSF Aβ levels in cognitively healthy individuals at risk for Alzheimer’s disease.” Mol Med 2011; 17(9-10):974-9.
  8. Ma Z, Siebert AP, Cheung KH, Lee RJ, Johnson B, Cohen AS, Vingtdeux V, Marambaud P, Foskett JK. “Calcium homeostasis modulator 1 (CALHM1) is the pore-forming subunit of an ion channel that mediates extracellular Ca2+ regulation of neuronal excitability.” PNAS 2012 Jul 10; 109(28): E1963-71.
  9. Dreses-Werringloer U, Vingtdeux V, Zhao H, Chandakkar P, Davies P, Marambaud P. “CALHM1 controls Ca2+-dependent MEK/ERK/RSK/MSK signaling in neurons.” J Cell Sci 2013; in press.
  10. Taruno A, Vingtdeux V, Ohmoto M, Ma Z, Dvoryanchikov G, Li A, Adrien L, Zhao H, Leung S, Abernethy M, Koppel K, Davies P, Civan M, Chaudhari N, Matsumoto H, Hellekant G, Tordoff M, Marambaud P#, Foskett JK# (#co-senior/co-corresponding authors). “CALHM1 ion channel mediates purinergic neurotransmission of sweet, bitter and umami tastes.” Nature 2013; in press.

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