Alternative processing of γ-secretase substrates in common forms of mild cognitive impairment and alzheimer's disease: Evidence for γ-secretase dysfunction
✍ Scribed by Saori Hata; Sayaka Fujishige; Yoichi Araki; Miyako Taniguchi; Katsuya Urakami; Elaine Peskind; Hiroyasu Akatsu; Masahiko Araseki; Kazuo Yamamoto; Ralph N. Martins; Masahiro Maeda; Masaki Nishimura; Allan Levey; Kathryn A. Chung; Thomas Montine; James Leverenz; Anne Fagan; Alison Goate; Randall Bateman; David M. Holtzman; Tohru Yamamoto; Tadashi Nakaya; Sam Gandy; Toshiharu Suzuki
- Publisher
- John Wiley and Sons
- Year
- 2011
- Tongue
- English
- Weight
- 331 KB
- Volume
- 69
- Category
- Article
- ISSN
- 0364-5134
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✦ Synopsis
Objective: The most common pathogenesis for familial Alzheimer's disease (FAD) involves misprocessing (or alternative processing) of the amyloid precursor protein (APP) by c-secretase due to mutations of the presenilin 1 (PS1) gene. This misprocessing/alternative processing leads to an increase in the ratio of the level of a minor csecretase reaction product (Ab42) to that of the major reaction product (Ab40). Although no PS1 mutations are present, altered Ab42/40 ratios are also observed in sporadic Alzheimer's disease (SAD), and these altered ratios apparently reflect deposition of Ab42 as amyloid. Methods: Using immunoprecipitation-mass spectrometry with quantitative accuracy, we analyzed in the cerebrospinal fluid (CSF) of various clinical populations the peptide products generated by processing of not only APP but also an unrelated protein, alcadein (Alc). Alc undergoes metabolism by the identical APP a-secretases and c-secretases, yielding a fragment that we have named p3-Alc a because of the parallel genesis of p3-Alc a peptides and the p3 fragment of APP. As with Ab, both major and minor p3-Alc a s are generated. We studied the alternative processing of p3-Alc a in various clinical populations.