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

EMBO Molecular Medicine
Nobuto KakudaJapanese Alzheimer's Disease Neuroimaging Initiative

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.

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Citations

Nov 21, 2013·Acta Neuropathologica Communications·María-Salud García-AyllónJavier Sáez-Valero
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Aug 9, 2018·ACS Omega·Frederick HsuZhefeng Guo
Nov 4, 2021·Translational Psychiatry·Nobuto KakudaTakeshi Ikeuchi

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Methods Mentioned

BETA
enzyme-linked immunosorbent assays
ELISA
ELISAs
immunoprecipitation
electrophoresis

Software Mentioned

SPSS

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