Generation of amyloid beta protein from a presenilin-1 and betaAPP complex |
| |
Authors: | Shizuka-Ikeda Masami Matsubara Etsuro Ikeda Masaki Kanai Mitsuyasu Tomidokoro Yasushi Ikeda Yoshio Watanabe Mitsunori Kawarabayashi Takeshi Harigaya Yasuo Okamoto Koichi Maruyama Kei Castaño Eduardo M St George-Hyslop Peter Shoji Mikio |
| |
Institution: | Department of Neurology, Gunma University School of Medicine, Maebashi, Gunma, Japan. |
| |
Abstract: | Presenilin-1 (PS1) is a causative gene in early onset familial Alzheimer's disease (FAD). FAD-linked mutant PS1s significantly increased Abeta40 and Abeta42(43) levels (P < 0.001) and decreased the production of an 11.4 kD (beta-stub) and an 8.7 kD (alpha-stub) carboxyl-terminal fragment of amyloid beta precursor protein (betaAPP-CTFs) (P < 0.01). In the 2% CHAPS extracted lysates, the complex containing the amino-terminal fragment of PS1 (PS1-NTF), the carboxyl-terminal fragments of PS1 (PS1-CTF), and betaAPP-CTFs was identified. Incubation of this isolated complex at pH 6.4 showed the direct generation of Abeta40 and gamma-stub from this complex. This reaction was inhibited by a gamma-secretase inhibitor. The degrading rate of a co-precipitated beta-stub was facilitated under the presence of FAD-linked mutant PS1s. This findings suggest that the direct generation of Abeta from the complex may play an important role in the pathogenesis of Alzheimer's disease. |
| |
Keywords: | Presenilin-1 γ-secretase βAPP Aβ40 Aβ42(43) PS1/βAPP complex |
本文献已被 ScienceDirect PubMed 等数据库收录! |