Elsevier

Neuroscience Letters

Volume 215, Issue 3, 13 September 1996, Pages 173-176
Neuroscience Letters

Amino- and carboxyl-terminal heterogeneity of β-amyloid peptides deposited in human brain

https://doi.org/10.1016/0304-3940(96)12970-0Get rights and content

Abstract

We aimed to determine quantitatively the fine amino- and carboxyl-terminal structure of Aβ peptides deposited in human brain using a set of 12 anti-Aβ antibodies that distinguish between terminal modifications including isomerization, stereoisomerization, limited proteolysis, and cyclization. Immunochemical examination of cortical blocks from aged subjects distinguished by their total plaque load and from a young Down's syndrome patient identified the major invariantly deposited species as AβX−42 (X = 1 (d-aspartate) and 3(pyroglutamate) and/or 11(pyroglutamate)). These molecular forms, presumably representing by-products of metabolic intermediates toward degradation, are similar in being resistant to major aminopeptidases. Aβ17–42 (‘p3’ fragment), a major secreted form of truncated Aβ with high insolubility, was found to be a minor one. A possible interpretation for these observations would be that proteolysis of Aβ from its amino terminus may limit the rate of Aβ catabolism.

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    In AD, the N-terminal's first two or ten amino acids of Aβ(1–42) can be cut off by secretase and aminopeptidase, producing Aβ(3–40/42) and Aβ(11–40/42) (Fig. 2) (Bien et al., 2012; Tsuda et al., 2017), resulting in more vulnerable 3rd or 11th glutamate to be cyclized by sQC into pyroglutamate. This pyroglutamate causes the formation of Aβ3 (pE)-40/42 and Aβ11 (pE)-40/42, in which truncated N-terminal and pyroglutamate modified Aβs starting at the 3rd or the 11th amino acid and ending at the 40th or the 42nd amino acid (Liu et al., 2006; Näslund et al., 1994; Russo et al., 2000; Saido et al., 1995, 1996; Schilling et al., 2008c; Wirths et al., 2009). Additionally, it has been shown that pE-Aβ is strongly correlated with AD progression (Jawhar et al., 2011; Schilling et al., 2008c), especially in the early stage (Hartlage-Rübsamen et al., 2011; Morawski et al., 2014), and pE-Aβ has been suggested to be a trigger of AD (Nussbaum et al., 2012).

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This work was supported in part by research grants from the Naito Foundation, the Uehara Foundation, the Tokyo Metropolitan Institute of Gerontology, and the Ministry of Education, Science, and Culture of Japan.

We thank Drs. Y. Ihara, K. Yanagisawa, and H. Shimada for indispensable support and discussion and Dr. S. Tsubuki for technical assistance. We also thank Dr. D.J. Selkoe and Dr. T. Aoyagi for valuable comments.

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