Role of Amyloid-β Glycine 33 in Oligomerization, Toxicity, and Neuronal Plasticity

被引:89
作者
Harmeier, Anja [1 ]
Wozny, Christian [2 ]
Rost, Benjamin R. [2 ]
Munter, Lisa-Marie [1 ]
Hua, Haiqing [3 ]
Georgiev, Oleg [3 ]
Beyermann, Michael [4 ]
Hildebrand, Peter W. [5 ]
Weise, Christoph [1 ]
Schaffner, Walter [3 ]
Schmitz, Dietmar [2 ]
Multhaup, Gerd [1 ]
机构
[1] Free Univ Berlin, Inst Chem & Biochem, D-14195 Berlin, Germany
[2] Charite Univ Med Berlin, Neurowissensch Forschungszentrum, D-10117 Berlin, Germany
[3] Univ Zurich, Inst Mol Biol, CH-8057 Zurich, Switzerland
[4] Leibniz Inst Mol Pharmacol, D-13125 Berlin, Germany
[5] Charite Univ Med Berlin, Inst Med Phys & Biophys, D-10117 Berlin, Germany
关键词
LONG-TERM POTENTIATION; PRECURSOR PROTEIN APP; ALZHEIMERS-DISEASE; SYNAPTIC PLASTICITY; IN-VIVO; SECONDARY STRUCTURE; TRANSGENIC MICE; NATURAL OLIGOMERS; COMMON MECHANISM; GXXXG MOTIFS;
D O I
10.1523/JNEUROSCI.1336-09.2009
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The aggregation of the amyloid-beta (A beta) peptide plays a pivotal role in the pathogenesis of Alzheimer's disease, as soluble oligomers are intimately linked to neuronal toxicity and inhibition of hippocampallong-term potentiation (LTP). In the C-terminal region of A beta there are three consecutive GxxxG dimerization motifs, which we could previously demonstrate to play a critical role in the generation of A beta. Here, we show that glycine 33 (G33) of the central GxxxG interaction motif within the hydrophobic A beta sequence is important for the aggregation dynamics of the peptide. A beta peptides with alanine or isoleucine substitutions of G33 displayed an increased propensity to form higher oligomers, which we could attribute to conformational changes. Importantly, the oligomers of G33 variants were much less toxic than A beta(42) wild type (WT), in vitro and in vivo. Also, whereas A beta(42) WT is known to inhibit LTP, A beta(42) G33 variants had lost the potential to inhibit LTP. Our findings reveal that conformational changes induced by G33 substitutions unlink toxicity and oligomerization of A beta on the molecular level and suggest that G33 is the key amino acid in the toxic activity of A beta. Thus, a specific toxic conformation of A beta exists, which represents a promising target for therapeutic interventions.
引用
收藏
页码:7582 / 7590
页数:9
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