209 Presenilin-1: A Component of Synaptic and Endothelial Adherens Junctions ANASTASIOS GEORGAKOPOULOS, a PHILIPPE MARAMBAUD, a VICTOR L. FRIEDRICH, JR., b JUNICHI SHIOI, a SPIROS EFTHIMIOPOULOS, a AND NIKOLAOS K. ROBAKIS a,c a Department of Psychiatry and Fishberg Research Center for Neurobiology, and b Departments of Biochemistry and Molecular Biology, Mount Sinai School of Medicine, New York, New York 10029, USA Presenilin-1 (PS1) is an integral membrane protein involved in the development of familial Alzheimer disease (FAD). Cadherin-based cell-cell interactions control crit- ical events in cell-cell adhesion and recognition. We obtained evidence that PS1 ac- cumulates at cell-cell contact sites where it colocalizes with components of the cadherin-based adherens junctions. At these sites, PS1 is linked to the cortical cy- tosksleton and is found at intercellular junctions. PS1 fragments form detergent- stable complexes with E-cadherin, β-catenin, and α-catenin, all components of ad- herens junctions. PS1 overexpression in human kidney cells enhances cell-cell adhesion. Together, our data show that PS1 incorporates into the cadherin/catenin adhesion system and modulates cell-cell adhesion. PS1 concentrates at synaptic con- tacts and forms complexes with brain E- and N-cadherin, known synaptic compo- nents. The PS1 incorporation into the cadherin/catenin complex makes it a potential target for PS1 FAD mutations. 1 Presenilin-1 (PS1) mutations are responsible for most cases of early-onset auto- somal dominant familial Alzheimer disease (FAD). PS1 protein is a polytopic trans- membrane peptide expressed in many tissues including brain where it is enriched in neurons. Structural studies suggest that PS1 crosses the membrane six or eight times with the N- and C-termini and the large hydrophilic loop all located in the cytoplasm. PS1 has been mainly localized in the endoplasmic reticulum (ER)/Golgi system and in vesicular structures. Most cellular full-length PS1 is cleaved within the large cyto- plasmic loop to yield N-terminal fragments of approximately 30 kDa and C-terminal fragments of approximately 20 kDa. Following cleavage of the full-length protein, PS1 fragments stay together as a stable 1:1 heterodimer. Recently it was shown that PS1 binds members of the armadillo family of proteins including δ- and β-catenin and promotes processing and signaling of Notch1 receptor. Other studies suggest that PS1 functions in protein trafficking, neuroprotection, chromosome segregation, and processing of selected proteins including APP (for a comprehensive review and ref- erence list of the cellular biology of PS1, see Ref. 3). Theories proposed to explain the mechanism by which PS1 mutations induce FAD include increased production c Address for correspondence: Dr. Nikolaos K. Robakis, Dept. of Psychiatry and Fishberg Research Center for Neurobiology, Mount Sinai School of Medicine, Box 1229, One Gustave Levy Place, New York, NY 10029-6547. Tel.: (212) 241-9380; fax: (212) 831-1947. e-mail: nikolaos.robakis@mssm.edu