Altered γ-secretase activity in mild cognitive impairment and Alzheimer's disease

Nobuto Kakuda, Mikio Shoji, Hiroyuki Arai, Katsutoshi Furukawa, Takeshi Ikeuchi, Kohei Akazawa, Mako Takami, Hiroyuki Hatsuta, Shigeo Murayama, Yasuhiro Hashimoto, Masakazu Miyajima, Hajime Arai, Yu Nagashima, Haruyasu Yamaguchi, Ryozo Kuwano, Kazuhiro Nagaike, Yasuo Ihara

Research output: Contribution to journalArticlepeer-review

47 Citations (Scopus)


We investigated why the cerebrospinal fluid (CSF) concentrations of Aβ42 are lower in mild cognitive impairment (MCI) and Alzheimer's disease (AD) patients. Because Aβ38/42 and Aβ40/43 are distinct product/precursor pairs, these four species in the CSF together should faithfully reflect the status of brain γ-secretase activity, and were quantified by specific enzyme-linked immunosorbent assays in the CSF from controls and MCI/AD patients. Decreases in the levels of the precursors, Aβ42 and 43, in MCI/AD CSF tended to accompany increases in the levels of the products, Aβ38 and 40, respectively. The ratios Aβ40/43 versus Aβ38/42 in CSF (each representing cleavage efficiency of Aβ43 or Aβ42) were largely proportional to each other but generally higher in MCI/AD patients compared to control subjects. These data suggest that γ-secretase activity in MCI/AD patients is enhanced at the conversion of Aβ43 and 42 to Aβ40 and 38, respectively. Consequently, we measured the in vitro activity of raft-associated γ-secretase isolated from control as well as MCI/AD brains and found the same, significant alterations in the γ-secretase activity in MCI/AD brains.

Original languageEnglish
Pages (from-to)344-352
Number of pages9
JournalEMBO Molecular Medicine
Issue number4
Publication statusPublished - 2012 Apr


  • Amyloid β-protein
  • CSF
  • Stepwise processing
  • γ-secretase

ASJC Scopus subject areas

  • Molecular Medicine


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