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

Nobuto Kakuda1, Mikio Shoji, Hiroyuki Arai

  • 1Immuno-Biological Laboratories Co., Fujioka, Japan.

EMBO Molecular Medicine
|February 23, 2012
PubMed

Insights

Cerebrospinal fluid (CSF) Aβ42 levels are lower in mild cognitive impairment (MCI) and Alzheimer's disease (AD) due to enhanced brain γ-secretase activity, leading to increased Aβ40 and Aβ38 production.

Area of Science:

  • Neuroscience
  • Biochemistry

Background:

  • Amyloid-beta (Aβ) peptides are central to Alzheimer's disease (AD) pathology.
  • Reduced cerebrospinal fluid (CSF) Aβ42 is a hallmark of mild cognitive impairment (MCI) and AD.
  • The precise mechanism behind decreased CSF Aβ42 in MCI/AD remains unclear.

Purpose of the Study:

  • To investigate the role of γ-secretase activity in the altered CSF Aβ profiles observed in MCI and AD patients.
  • To determine if altered γ-secretase activity contributes to the decrease in CSF Aβ42 levels.

Main Methods:

  • Quantification of four Aβ species (Aβ38, Aβ40, Aβ42, Aβ43) in CSF from controls, MCI, and AD patients using enzyme-linked immunosorbent assays.
  • Analysis of Aβ precursor/product ratios to infer γ-secretase cleavage efficiency.
  • In vitro measurement of γ-secretase activity in brain homogenates from control and MCI/AD individuals.

Main Results:

  • CSF levels of Aβ42 and Aβ43 (precursors) were decreased in MCI/AD patients.
  • CSF levels of Aβ38 and Aβ40 (products) showed a tendency to increase in MCI/AD patients.
  • Ratios indicating Aβ43 and Aβ42 cleavage efficiency by γ-secretase were significantly higher in MCI/AD patients.
  • In vitro assays confirmed enhanced γ-secretase activity in brain tissue from MCI/AD patients.

Conclusions:

  • Enhanced γ-secretase activity in the brain contributes to the reduced CSF Aβ42 levels seen in MCI and AD.
  • This increased activity promotes the conversion of Aβ42 and Aβ43 into Aβ38 and Aβ40.
  • Altered γ-secretase function is a key factor in the amyloid pathology of MCI and AD.

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