TY - JOUR
T1 - Altered γ-secretase activity in mild cognitive impairment and Alzheimer's disease
AU - Kakuda, Nobuto
AU - Shoji, Mikio
AU - Arai, Hiroyuki
AU - Furukawa, Katsutoshi
AU - Ikeuchi, Takeshi
AU - Akazawa, Kohei
AU - Takami, Mako
AU - Hatsuta, Hiroyuki
AU - Murayama, Shigeo
AU - Hashimoto, Yasuhiro
AU - Miyajima, Masakazu
AU - Arai, Hajime
AU - Nagashima, Yu
AU - Yamaguchi, Haruyasu
AU - Kuwano, Ryozo
AU - Nagaike, Kazuhiro
AU - Ihara, Yasuo
PY - 2012/4
Y1 - 2012/4
N2 - 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.
AB - 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.
KW - Amyloid β-protein
KW - CSF
KW - NSAID
KW - Stepwise processing
KW - γ-secretase
UR - http://www.scopus.com/inward/record.url?scp=84859379937&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84859379937&partnerID=8YFLogxK
U2 - 10.1002/emmm.201200214
DO - 10.1002/emmm.201200214
M3 - Article
C2 - 22354516
AN - SCOPUS:84859379937
VL - 4
SP - 344
EP - 352
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
SN - 1757-4676
IS - 4
ER -