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: Presenilin 1/2 make up the catalytic site of γ-secretase. The enzymatic properties of γ-secretase that cleave the transmembrane domain of βCTF have been an enigma, although recent studies provided partial elucidation of this mechanism (Qi-Takahara et al, 2005; Takami et al, 2009). γ-Secretase has two product lines, which successively convert the Aβ49 and Aβ48 that are generated by ε-cleavage, to shorter Aβs by releasing tri- or tetrapeptides in a stepwise fashion. Aβ49 is successively cleaved mostly into Aβ40 via Aβ46 and Aβ43, while Aβ48 is similarly cleaved into Aβ38 via Aβ45 and Aβ42 (see Fig 1). Importantly, the differences between the amounts of released tri- and tetrapeptides determine the levels of the different Aβ species produced (Takami et al, 2009). Thus, the true activity of γ-secretase is defined by the amounts of tri- and tetrapeptides released, but not by the amounts of Aβ species produced. Of note, the most abundant species Aβ40 is derived not from Aβ42, but from Aβ43. Also Aβ38 is derived mainly from Aβ42 (Fig 1). The longer Aβs in cerebrospinal fluid (CSF) including Aβ49 and 46 as well as Aβ48 and 45 must be generated at negligible levels, but may neither be secreted to the interstitial fluid (ISF) nor recruited to CSF. This suggests that the status of brain, and possibly neuronal, γ-secretase could be accurately assessed by measuring all four Aβ species generated by the two product lines of γ-secretase.
Affiliation: Immuno-Biological Laboratories Co., Fujioka, Japan.