Elucidating Molecular Mass and Shape of a Neurotoxic A尾 Oligomer

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• 作者：Adriano Sebollela ; Gina-Mirela Mustata ; Kevin Luo ; Pauline T. Velasco ; Kirsten L. Viola ; Erika N. Cline ; Gajendra S. Shekhawat ; Kyle C. Wilcox ; Vinayak P. Dravid ; William L. Klein
• 刊名：ACS Chemical Neuroscience
• 出版年：2014
• 出版时间：December 17, 2014
• 年：2014
• 卷：5
• 期：12
• 页码：1238-1245
• 全文大小：340K
• ISSN：1948-7193

文摘

Alzheimer's disease (AD), the most prevalent type of dementia, has been associated with the accumulation of amyloid 尾 oligomers (A尾Os) in the central nervous system. A尾Os vary widely in size, ranging from dimers to larger than 100 kDa. Evidence indicates that not all oligomers are toxic, and there is yet no consensus on the size of the actual toxic oligomer. Here we used NU4, a conformation-dependent anti-A尾O monoclonal antibody, to investigate size and shape of a toxic A尾O assembly. By using size-exclusion chromatography and immuno-based detection, we isolated an A尾O-NU4 complex amenable for biochemical and morphological studies. The apparent molecular mass of the NU4-targeted oligomer was 80 kDa. Atomic force microscopy imaging of the A尾O-NU4 complex showed a size distribution centered at 5.37 nm, an increment of 1.5 nm compared to the size of A尾Os (3.85 nm). This increment was compatible with the size of NU4 (1.3 nm), suggesting a 1:1 oligomer to NU4 ratio. NU4-reactive oligomers extracted from AD human brain concentrated in a molecular mass range similar to that found for in vitro prepared oligomers, supporting the relevance of the species herein studied. These results represent an important step toward understanding the connection between A尾O size and toxicity.

Keywords:

A尾 oligomer; Alzheimer鈥檚 disease; NU4 antibody; neurotoxicity; AFM