title: Altered γ-secretase activity in mild cognitive impairment and Alzheimer's disease.
abstract: 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.
authors.affiliation: Immuno-Biological Laboratories Co., Fujioka, Japan.
authors.forename: Nobuto
authors.initials: N
authors.lastname: Kakuda
authors.forename: Mikio
authors.initials: M
authors.lastname: Shoji
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Furukawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ikeuchi
authors.forename: Kohei
authors.initials: K
authors.lastname: Akazawa
authors.forename: Mako
authors.initials: M
authors.lastname: Takami
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hatsuta
authors.forename: Shigeo
authors.initials: S
authors.lastname: Murayama
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Masakazu
authors.initials: M
authors.lastname: Miyajima
authors.forename: Hajime
authors.initials: H
authors.lastname: Arai
authors.forename: Yu
authors.initials: Y
authors.lastname: Nagashima
authors.forename: Haruyasu
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Ryozo
authors.initials: R
authors.lastname: Kuwano
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nagaike
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ihara
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000201:enzymology*; D053829:Amyloid Precursor Protein Secretases / Q000134:cerebrospinal fluid* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid / Q000201:enzymology*; D005260:Female; D006801:Humans; D008297:Male
chemical_list: D016229:Amyloid beta-Peptides; D053829:Amyloid Precursor Protein Secretases