Ratna Sircar, PhD Lab Head

In an attempt to understand developmental neuroplasticity and the neural adaptations underlying cognitive dysfunctions associated with exposure to illicit substances during brain development, Ratna Sircar, PhD, and her colleagues have shown that the adolescent brain is particularly sensitive to substances of abuse.
 
Compared to the perinatal brain or the adult brain, the adolescent brain responds differently to alcohol and other substances such as gamma-hydroxybutyric acid (GHB). They are now trying to figure out the mechanisms that make the adolescent brain so vulnerable. Dr. Sircar is also interested in the pathophysiology underlying schizophrenia.
 
Cognitive deficits in executive functioning, attention, working memory, problem-solving and verbal learning skills are commonly observed in patients with schizophrenia. In fact, cognitive impairments are thought to be of greater importance in predicting functional outcomes than improvements in hallucinations and delusions or negative symptoms. Understanding the molecular mechanisms underlying the cognitive deficits could form the basis for the development of novel strategies to treat and/or prevent this mental illness.
 

		Name:   Licheng Wu Position:   Research Assistant Email:   liwu@nshs.edu
		Name:   Krishna Reddy Position:   Research Assistant Email:   kreddy@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/-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.