Secreted Amyloid 尾-Proteins in a Cell Culture Model Include N-Terminally Extended Peptides That Impair Synaptic Plasticity
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- 作者：Alfred T. Welzel ; John E. Maggio ; Ganesh M. Shankar ; Donald E. Walker ; Beth L. Ostaszewski ; Shaomin Li ; Igor Klyubin ; Michael J. Rowan ; Peter Seubert ; Dominic M. Walsh ; Dennis J. Selkoe
- 刊名：Biochemistry
- 出版年：2014
- 出版时间：June 24, 2014
- 年：2014
- 卷：53
- 期：24
- 页码：3908-3921
- 全文大小：600K
- ISSN：1520-4995
文摘
Evidence for a central role of amyloid 尾-protein (A尾) in the genesis of Alzheimer鈥檚 disease (AD) has led to advanced human trials of A尾-lowering agents. The 鈥渁myloid hypothesis鈥?of AD postulates deleterious effects of small, soluble forms of A尾 on synaptic form and function. Because selectively targeting synaptotoxic forms of soluble A尾 could be therapeutically advantageous, it is important to understand the full range of soluble A尾 derivatives. We previously described a Chinese hamster ovary (CHO) cell line (7PA2 cells) that stably expresses mutant human amyloid precursor protein (APP). Here, we extend this work by purifying an sodium dodecyl sulfate (SDS)-stable, 8 kDa A尾 species from the 7PA2 medium. Mass spectrometry confirmed its identity as a noncovalently bonded A尾40 homodimer that impaired hippocampal long-term potentiation (LTP) in vivo. We further report the detection of A尾-containing fragments of APP in the 7PA2 medium that extend N-terminal from Asp1 of A尾. These N-terminally extended A尾-containing monomeric fragments are distinct from soluble A尾 oligomers formed from A尾1-40/42 monomers and are bioactive synaptotoxins secreted by 7PA2 cells. Importantly, decreasing 尾-secretase processing of APP elevated these alternative synaptotoxic APP fragments. We conclude that certain synaptotoxic A尾-containing species can arise from APP processing events N-terminal to the classical 尾-secretase cleavage site.