Presenilin1 (PS1) is an integral membrane protein involved in the development of familial Alzheimer disease (FAD). PS1 is processed intracellularly into N and C-terminal fragments. Classic cadherins are type I transmembrane glycoproteins that control critical events in cell-cell adhesion and recognition. Cadherin-based cell adhesion is mediated by catenins, which are cytosolic proteins that link surface cadherin to the cortical cytoskeleton. We used confocal microscopy to show that in cell cultures PS1 accumulates at cell-cell contact sites. At these sites, PS1 colocalizes with components of the cadherin-based adherens junctions and is linked to the cortical cytoskeleton. Both PS1 fragments form complexes with components of the cadherin-based adhesion system including E-cadherin, beta- catenin, gamma-catenin, and alpha-catenin. Furthermore, PS1 fragments are found in a single complex with E-cadherin and beta- catenin. PS1 forms complexes with cell surface E-cadherin, and in epithelial tissue it concentrates at cell-cell contact sites. Together, these data show that PS1 incorporates into the cadherin/catenin adhesion system where it probably functions in cell-cell adhesion and recognition. In the brain, PS1 fragments form complexes with cadherins which are known components of the synapse. Thus, PS1 mutations may act in FAD through disruption of cadherin-based cell-cell interactions. Based on these findings, we propose to define the bindings between PS1 and other components of the cadherin-based adhesion system and to explore how PS1 FAD mutants affect these bindings. We will also examine whether PS1 functions in cadherin-based cell-cell adhesion, and define the effects of FAD mutations on PS1 function. Finally, we will examine whether PS1 is part of the cadherin/catenin apparatus at the synapse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG017926-02
Application #
6372467
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Snyder, D Stephen
Project Start
2000-05-01
Project End
2005-04-30
Budget Start
2001-05-01
Budget End
2002-04-30
Support Year
2
Fiscal Year
2001
Total Cost
$339,000
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Psychiatry
Type
Schools of Medicine
DUNS #
114400633
City
New York
State
NY
Country
United States
Zip Code
10029
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