Gender	Male
E-mail	nikos.robakis@mssm.edu
Education and Training	Ph.D., New York University

Dr. Robakis is A.P. Slaner Professor for Alzheimer's Disease Research and is Director of the Center for Molecular Biology and Genetics of Neurodegeneration.

Training Areas: Neurobiology, Molecular Biology, Molecular Basis of Disease.

Education and Training	Ph.D., New York University

Genetics and function of proteins involved in neurodegeneration (APP, presenilin, tau)

Neurodegenerative disorders are characterized by a chronic, progressive, and selective loss of neurons in cognitive, sensory and motor systems. Alzheimer's disease (AD) is the most common cause of dementia in the aged and results from severe neuronal loss and synaptic abnormalities. AD is characterized by the accumulation of amyloid plaques and neurofibrillary tangles. Most AD cases lack an obvious genetic etiology and are characterized as "sporadic", whereas a smaller percent of all cases segregates within families (FAD) suggesting a genetic etiology. The genetic defects of most FAD cases map on three genes including the Amyloid precursor protein (APP) located on chromosome 21, and Presenilins 1 and 2 located on chromosomes 14 and 1 respectively. Proteolytic processing of APP results in the production of Abeta peptides that aggregate to form the amyloid depositions present in all AD forms. PS-1 mutations however, seem to be are responsible for most of the FAD cases. Presently, the mechanism by which APP and PS mutants promote neuronal cell death cause AD is not entirely clear, but it seems that the FAD mutations interfere with the biological function of proteins. A second possibility is that these FAD mutants acquire a new function detrimental to neurons including an increase in the production of Abeta peptides, the precursor of amyloid.

To understand the consequences of the FAD mutations on neurodegeneration, we study the genetics, molecular biology, and function of the wild type and mutant APP and PSs. Recently, we obtained evidence that PS1 is a component of the adherens junctions and regulates cell-cell adhesion and communication. PS-1 concentrates at synaptic contacts and forms complexes with brain N-cadherin, an important component of synaptic structures. PS1 controls proteolytic processing of cadherins and production of peptides with signal transduction functions. For example, the PS1-dependent cleavage of N-cadherin is regulated by NMDA receptor activity and the resulting peptide promotes degradation of CBP thus regulating CREB/CBP-dependent gene expression. Moreover, we showed recently that PS1 regulates the PI3K/Akt cell survival pathway. This is a new function of PS1 with potential applications in AD because this pathway plays central roles in neuronal survival (See Marambaud et al., 2003 and Baki et al., 2004). To answer our questions we use in vitro gene expression systems and transgenic mice expressing PS1 and APP mutants in their brains.

Center for Molecular Biology and Genetics of Neurodegeneration

Neve RL, Robakis NK. Alzheimer's disease: a re-examination of the amyloid hypothesis. Trends Neurosci (TINS) 1998 Jan; 21(1): 15-9.

Tsuchida K, Shioi J, Yamada S, Boghosian G, Wu A, Cai H, Sugahara K, Robakis NK. Appican, the Proteoglycan Form of the Amyloid Precursor Protein, Contains the Chondroitin Sulfate E Motif in the Repeating Disaccharide Region and a 4-O-Sulfated Galactose Residue in the Linkage Region. J Biol Chem 2001; 276: 37155-37160.

Baki L, Marambaud P, Efthimiopoulos S, Georgakopoulos A, Wen P, Cui W, Shioi, J, Koo E, Ozawa M, Friedrich Jr V, Robakis NK. Presenilin1 binds cytoplasmic epithelial cadherin, inhibits cadherin/p120 association, and regulates stability and function of the cadherin/catenin adhesion complex. Proc Natl Acad Sci U S A 2001 Feb 27; 98(5): 2381-86.

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

Marambaud P, Wen P, Shioi J, Siman R, Takashima A, Robakis N. 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.

Baki L, Shioi J, Wen P, Shao Z, Schwarzman A, Gamma-Sosa M, Neve R, Robakis NK. PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: effects of FAD mutations. EMBO J 2004; 23: 2586-2596.