Neuron-specific mechanism for production and secretion of amyloid-beta and therapeutic regulation of its deposition

2016 Fiscal Year Final Research Report

• Project/Area Number: 26430070
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Shiga University of Medical Science
• Principal Investigator: NISHIMURA Masaki 滋賀医科大学, 神経難病研究センター, 教授 (40322739)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 認知症 / アルツハイマー病 / アミロイドβ / シナプス / Presenilin / ILEI / γセクレターゼ

Outline of Final Research Achievements

The exact subcellular site and mechanism of Alzheimer disease-related Aβ secretion form neurons in vivo remain unresolved. (1) Using subcellular fractionation of mouse brain, we revealed that APP and components of the γ-secretase complex are localized to the active zone membrane and the active zone-docked synaptic vesicles of the presynaptic terminals. (2) We could not find any post-translational modification of synaptic Presenilin-1 which enhanced a relative ratio of Aβ42 production. (3) We found ILEI as a synaptic Aβ production-suppressing protein and tried molecular design for Aβ-reducing peptides or compounds by conformational prospect of the interaction between ILEI and Preseniin-1. We also found that this binding was dependent on the DQL sequence of Presenilin-1 C-terminal tail, and the 3 dimension-reference interaction site model (3D-RISM) theory predicted that candidate of Presenilin-1-binding region on ILEI is around a side chain of the Lys84 residue.

Free Research Field

分子神経病態学