Altered γ-secretase activity in mild cognitive impairment and Alzheimer's disease.
Bottom Line: 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.
Affiliation: Immuno-Biological Laboratories Co., Fujioka, Japan.Show MeSH
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Mentions: This relationship in γ-secretase cleavage becomes clearer by plotting the product/precursor ratio representing cleavage efficiency at the step from Aβ42 to 38 (Aβ38/42) against that representing the cleavage efficiency at the step from Aβ43 to 40 (Aβ40/43) (Fig 4). The ‘apparent’ cleavage efficiency of Aβ43 was approximately 40-fold larger than that of Aβ42. The two ratios in CSF samples from MCI/AD and control subjects were largely proportional to each other, indicating that the corresponding cleavage processes in the two lines are tightly coupled (Fig 4). All plots were situated on a distinct line [ln(Aβ38/42) = 0.748 × ln(Aβ40/43) − 2.244, R = 0.936] and its close surroundings. An increase in the cleavage from Aβ43 to 40 (i.e. more Aβ43 is converted to Aβ40) accompanied an increase in the cleavage from Aβ42 to 38 and vice versa, although the mechanism underlying this coupling between the two product lines remains unknown. This reminds us of the ‘NSAID effect’ in the 3-([3-cholamidopropyl]dimetylammonio)-2-hydroxy-1-propanesulfonate (CHAPSO)-reconstituted γ-secretase system (Takami et al, 2009; Weggen et al, 2001) in which the addition of sulindac sulfide to the γ-secretase reaction mixture, as expected, significantly suppressed Aβ42 production and increased Aβ38 production presumably by increasing the amounts of released tetrapeptide (VVIA) (Takami et al, 2009) and other peptides.
Affiliation: Immuno-Biological Laboratories Co., Fujioka, Japan.