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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 Aβ43 and 40, and between those of Aβ42 and 38 in CSF from controls (open circles) and MCI (closed triangle)/AD patients (closed circle)The levels of ln(Aβ43) correlate with those of ln(Aβ40) within controls (R = 0.688), and barely within MCI/AD subjects (R = 0.507/0.736). The plots for MCI/AD were located below the regression line for control (p < 0.001, ANOVA).The levels of Aβ42 correlate with those of Aβ38 within controls (R = 0.723), and barely within MCI/AD (R = 0.500/0.393). The plots for MCI/AD were situated below the regression line for controls (p < 0.001, ANOVA).
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fig03: Relationships between the levels of Aβ43 and 40, and between those of Aβ42 and 38 in CSF from controls (open circles) and MCI (closed triangle)/AD patients (closed circle)The levels of ln(Aβ43) correlate with those of ln(Aβ40) within controls (R = 0.688), and barely within MCI/AD subjects (R = 0.507/0.736). The plots for MCI/AD were located below the regression line for control (p < 0.001, ANOVA).The levels of Aβ42 correlate with those of Aβ38 within controls (R = 0.723), and barely within MCI/AD (R = 0.500/0.393). The plots for MCI/AD were situated below the regression line for controls (p < 0.001, ANOVA).

Mentions: Aβ42 and Aβ43 are produced by the second cleavage step of each product line. Like Aβ40 and Aβ38, the CSF concentrations of Aβ42 and Aβ43 are also proportional to each other in controls and in MCI/AD patients [Fig 2B; ln(Aβ43) = 1.333 × ln(Aβ42) − 4.09, R = 0.979]. On the other hand, the levels of Aβ43 and Aβ40 (a precursor and its product) were correlated in control [Fig 3A; ln(Aβ43) = 0.884 × ln(Aβ40) − 4.118, R = 0.688] and in MCI/AD subjects (R = 0.507/0.736 for MCI/AD, respectively) but the MCI/AD values were located below the regression line for controls and thus provided lower Aβ43 measures compared with controls for a given Aβ40 measure (Fig 3A; p < 0.001, analysis of variance, ANOVA). Conversely, for a given Aβ43 value, the plot provided a higher Aβ40 measure in MCI/AD cases. There was a similar situation for the levels of Aβ42 and Aβ38. The levels of Aβ42 and Aβ38 were correlated each other in control subjects [Fig 3B; ln(Aβ42) = 0.724 × ln(Aβ38) + 0.251, R = 0.723], but barely in MCI/AD (R = 0.500 for MCI; 0.393 for AD), and the MCI/AD plots were situated below the regression line for controls (p < 0.001, ANOVA). For a given Aβ42 value, the plot provided a higher Aβ38 measure in MCI/AD compared with controls.


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 Aβ43 and 40, and between those of Aβ42 and 38 in CSF from controls (open circles) and MCI (closed triangle)/AD patients (closed circle)The levels of ln(Aβ43) correlate with those of ln(Aβ40) within controls (R = 0.688), and barely within MCI/AD subjects (R = 0.507/0.736). The plots for MCI/AD were located below the regression line for control (p < 0.001, ANOVA).The levels of Aβ42 correlate with those of Aβ38 within controls (R = 0.723), and barely within MCI/AD (R = 0.500/0.393). The plots for MCI/AD were situated below the regression line for controls (p < 0.001, ANOVA).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3376855&req=5

fig03: Relationships between the levels of Aβ43 and 40, and between those of Aβ42 and 38 in CSF from controls (open circles) and MCI (closed triangle)/AD patients (closed circle)The levels of ln(Aβ43) correlate with those of ln(Aβ40) within controls (R = 0.688), and barely within MCI/AD subjects (R = 0.507/0.736). The plots for MCI/AD were located below the regression line for control (p < 0.001, ANOVA).The levels of Aβ42 correlate with those of Aβ38 within controls (R = 0.723), and barely within MCI/AD (R = 0.500/0.393). The plots for MCI/AD were situated below the regression line for controls (p < 0.001, ANOVA).
Mentions: Aβ42 and Aβ43 are produced by the second cleavage step of each product line. Like Aβ40 and Aβ38, the CSF concentrations of Aβ42 and Aβ43 are also proportional to each other in controls and in MCI/AD patients [Fig 2B; ln(Aβ43) = 1.333 × ln(Aβ42) − 4.09, R = 0.979]. On the other hand, the levels of Aβ43 and Aβ40 (a precursor and its product) were correlated in control [Fig 3A; ln(Aβ43) = 0.884 × ln(Aβ40) − 4.118, R = 0.688] and in MCI/AD subjects (R = 0.507/0.736 for MCI/AD, respectively) but the MCI/AD values were located below the regression line for controls and thus provided lower Aβ43 measures compared with controls for a given Aβ40 measure (Fig 3A; p < 0.001, analysis of variance, ANOVA). Conversely, for a given Aβ43 value, the plot provided a higher Aβ40 measure in MCI/AD cases. There was a similar situation for the levels of Aβ42 and Aβ38. The levels of Aβ42 and Aβ38 were correlated each other in control subjects [Fig 3B; ln(Aβ42) = 0.724 × ln(Aβ38) + 0.251, R = 0.723], but barely in MCI/AD (R = 0.500 for MCI; 0.393 for AD), and the MCI/AD plots were situated below the regression line for controls (p < 0.001, ANOVA). For a given Aβ42 value, the plot provided a higher Aβ38 measure in MCI/AD compared with controls.

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