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

Kakuda N, Shoji M, Arai H, Furukawa K, Ikeuchi T, Akazawa K, Takami M, Hatsuta H, Murayama S, Hashimoto Y, Miyajima M, Arai H, Nagashima Y, Yamaguchi H, Kuwano R, Nagaike K, Ihara Y, Japanese Alzheimer's Disease Neuroimaging Initiati - EMBO Mol Med (2012)

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.

View Article: PubMed Central - PubMed

Affiliation: Immuno-Biological Laboratories Co., Fujioka, Japan.

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Relationships between the levels of Aβ40 and 38, and between those of Aβ43 and 42 in CSF from controls and MCI/AD patientsThe levels of ln(Aβ40) were proportional to those of ln(Aβ38) (ln(Aβ40) = 0.910 × ln(Aβ38) + 1.642, R = 0.913).The levels of ln(Aβ43) were proportional to those of ln(Aβ42) (ln(Aβ43) = 1.333 × ln(Aβ42) − 4.09, R = 0.979). It should be noted that the levels of both ln(Aβ42) and ln(Aβ43) in MCI [filled triangle (n = 19)]/AD [filled circle (n = 24)] are lower than those in controls [open circles (n = 21)].
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fig02: Relationships between the levels of Aβ40 and 38, and between those of Aβ43 and 42 in CSF from controls and MCI/AD patientsThe levels of ln(Aβ40) were proportional to those of ln(Aβ38) (ln(Aβ40) = 0.910 × ln(Aβ38) + 1.642, R = 0.913).The levels of ln(Aβ43) were proportional to those of ln(Aβ42) (ln(Aβ43) = 1.333 × ln(Aβ42) − 4.09, R = 0.979). It should be noted that the levels of both ln(Aβ42) and ln(Aβ43) in MCI [filled triangle (n = 19)]/AD [filled circle (n = 24)] are lower than those in controls [open circles (n = 21)].

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.


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

Kakuda N, Shoji M, Arai H, Furukawa K, Ikeuchi T, Akazawa K, Takami M, Hatsuta H, Murayama S, Hashimoto Y, Miyajima M, Arai H, Nagashima Y, Yamaguchi H, Kuwano R, Nagaike K, Ihara Y, Japanese Alzheimer's Disease Neuroimaging Initiati - EMBO Mol Med (2012)

Relationships between the levels of Aβ40 and 38, and between those of Aβ43 and 42 in CSF from controls and MCI/AD patientsThe levels of ln(Aβ40) were proportional to those of ln(Aβ38) (ln(Aβ40) = 0.910 × ln(Aβ38) + 1.642, R = 0.913).The levels of ln(Aβ43) were proportional to those of ln(Aβ42) (ln(Aβ43) = 1.333 × ln(Aβ42) − 4.09, R = 0.979). It should be noted that the levels of both ln(Aβ42) and ln(Aβ43) in MCI [filled triangle (n = 19)]/AD [filled circle (n = 24)] are lower than those in controls [open circles (n = 21)].
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3376855&req=5

fig02: Relationships between the levels of Aβ40 and 38, and between those of Aβ43 and 42 in CSF from controls and MCI/AD patientsThe levels of ln(Aβ40) were proportional to those of ln(Aβ38) (ln(Aβ40) = 0.910 × ln(Aβ38) + 1.642, R = 0.913).The levels of ln(Aβ43) were proportional to those of ln(Aβ42) (ln(Aβ43) = 1.333 × ln(Aβ42) − 4.09, R = 0.979). It should be noted that the levels of both ln(Aβ42) and ln(Aβ43) in MCI [filled triangle (n = 19)]/AD [filled circle (n = 24)] are lower than those in controls [open circles (n = 21)].
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.

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.

View Article: PubMed Central - PubMed

Affiliation: Immuno-Biological Laboratories Co., Fujioka, Japan.

Show MeSH
Related in: MedlinePlus