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: The CSF concentrations of Aβs were in the following order: Aβ40 > Aβ38 > Aβ42 Aβ43 in all CSF samples examined (Table 1 and Supporting Information Fig S2A). The relative amounts of Aβs were constant across the samples: Aβ38:40 ratio in CSF was ∼1:3, and Aβ42:43 ratio was ∼10:1. The CSF concentrations of Aβ40 were significantly increased in AD compared to control (Table 1; p < 0.05, Dunnett's t-test). Additionally, the CSF concentrations of Aβ38 tended to be increased in AD patients compared to controls. In contrast, those of Aβ42 and 43 were significantly decreased in MCI/AD compared to controls (p < 0.05, Dunnett's t-test). Interestingly, as reported previously (Schoonenboom et al, 2005), the CSF concentrations of Aβ40 and Aβ38 were proportional to each other in all subjects [Fig 2A; ln(Aβ40) = 0.910 × ln(Aβ38) + 1.642, R = 0.913, where ln(Aβ40) is the logarithm of Aβ40], even in MCI/AD cases. This was despite the fact that these species are derived from and the final products of the two different product lines of γ-secretase activity (Fig 1; Takami et al, 2009). In other words, the amounts of products in the third step of cleavage were strictly proportional to each other across the product lines.
Affiliation: Immuno-Biological Laboratories Co., Fujioka, Japan.