Mechanism of presenilin/gamma secretase to produce amyloid beta

2016 Fiscal Year Final Research Report

• Project/Area Number: 26461746
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Osaka University
• Principal Investigator: Tagami Shinji 大阪大学, 医学系研究科, 助教 (40362735)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: アルツハイマー病 / γセクレターゼ / アミロイドβ / プレセニリン / APL1β / アルツハイマー病バイオマーカー / γ切断

Outline of Final Research Achievements

Beta APP-CTF stubs undergo endoproteolysis by gamma secretase at the epsilon cleavage sites. Gamma secretase sequentially cleaves the resultant substrate every some amino acid residues, thus generating secreted Abeta. We could quantify the small residual peptides generated during sequential cleavages upon Abeta production inside the cells. By this analysis, we could evaluate the activity of gamma secretase to produce amyloid beta.
Substantial amounts of Abeta42 accumulate in brains of Presenilin 1 (PS1) mutations-associated with familial AD(FAD). We analyzed CSF APL1beta levels, a non-amyloidogenic surrogate marker of Abeta42 in PS1-FAD patients and in non AD controls. Importantly, CSF APL1beta28 was not significantly higher. However, shorter CSF APL1beta25/27 were significantly lower in PS1-FAD patients. There data suggest that in PS1-FAD patients massive Abeta42 accumulation in PS1-FAD brain occurs without an apparent increase in Abeta42 secretion.

Free Research Field

アルツハイマー病研究