Altered ?-secretase activity in mild cognitive impairment and Alzheimer%26apos;s disease

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

来源：EMBO Molecular Medicine, 2012, 4(4): 344-352.

DOI：10.1002/emmm.201200214

• amyloid ss-protein
• CSF
• -secretase
• NSAID
• stepwise processing

We investigated why the cerebrospinal fluid (CSF) concentrations of A beta 42 are lower in mild cognitive impairment (MCI) and Alzheimer%26apos;s disease (AD) patients. Because A beta 38/42 and A beta 40/43 are distinct product/precursor pairs, these four species in the CSF together should faithfully reflect the status of brain gamma-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, A beta 42 and 43, in MCI/AD CSF tended to accompany increases in the levels of the products, A beta 38 and 40, respectively. The ratios A beta 40/43 versus A beta 38/42 in CSF (each representing cleavage efficiency of A beta 43 or A beta 42) were largely proportional to each other but generally higher in MCI/AD patients compared to control subjects. These data suggest that gamma-secretase activity in MCI/AD patients is enhanced at the conversion of A beta 43 and 42 to A beta 40 and 38, respectively. Consequently, we measured the in vitro activity of raft-associated gamma-secretase isolated from control as well as MCI/AD brains and found the same, significant alterations in the gamma-secretase activity in MCI/AD brains.

• 出版日期2012-4