Intersection between familial Alzheimer's disease and Notch signal transduction pathway

1997 Fiscal Year Final Research Report Summary

• Project/Area Number: 08680845
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Yokohama City University
• Principal Investigator: NAKAI Toshiki Yokohama City University, School of Medicine, Assistant professor, 医学部, 助手 (20270712)
• Co-Investigator(Kenkyū-buntansha): AMAYA Yoshihiro Niigata University, School of Dentist, Assistant professor, 歯学部, 助手 (50193032) ; MIURA Satoshi Yokohama City University, School of Medicine, Associate professor, 医学部, 助教授 (60157427)
• Project Period (FY): 1996 – 1997
• Keywords: presenilin / Alzheimer's disease / Notch / membrane protein / membrane topology

Research Abstract

Chromosomal mutations in the gene for presenilin-1 or presenilin-2 are known to cause early-onset familial Alzheimer's disease (AD). From genetic analysis of C.elegans and phenotypical analysis of presenilin-1 knock-out mice, presenilins are also implicated to be involved in the Notch signal transduction pathway, which is important to the regulation of cell differentiation. For the first step to elucidate the molecular function of presenilins, which are situated in the intersection between AD and Notch pathway, and further to assess the possibility of Notch pathway involvement in the etiology of AD,we studied the membrane topology of presenilin-1 in detail. We also examined the possible physical interaction between presenilin-1 and Notch molecule using yeast two-hybrid system.
1.Membrane topological analysis of presenilin : Membrane topology of presenilin-1 was studied by expressing a series of fusion proteins between C-terminal deleted presenilin-1 and a reporter in in vitro transcription-translation system and examining N-glycosylation and protection against proteinase K in the presence of microsomal membrane. Our results indicated that the structure of its C-terminal portion is different from those suggested by other groups. Based on the results of this study, we propose the "seven-spanning and one-embedded" model for presenilin membrane topology.
2.Analysis of the interaction between presenilin-1 and Notch-1 : Yeast two-hybrid analysis was employed to assess possible direct interaction between the n-terminal, hydrophilic loop or C-terminal region of presenilin-1 and the cytosolic region of Notch-1. Our result excluded the possibility of physical interaction between presenilin-1 and, at least, the cytosolic region of Notch-1.