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- W2080309385 abstract "Amyloid-β (Aβ) peptide is generated by the proteolytic cleavage of amyloid precursor protein (APP) by β- and γ-secretases. γ-secretase inhibitors (GSI) inhibit proteolytic cleavage at the γ-sites and reduce the production of Aβ peptides. In contrast, γ-secretase modulators (GSM) shift the cleavage sites to produce shorter Aβ peptides, such as Aβ 37 and 38, but reduced longer amyloidogenic Aβ 40 and 42 peptides. In both preclinical and clinical studies it has been shown that single administration of GSI produces a paradoxical increase in plasma Aβ levels beyond the baseline, “Aβ overshoot”, after an initial transient decrease. In this study, we tested whether GSM would cause an Aβ overshoot in rats and compare its effect on APP processing with that of GSI. Sprague-Dawley rats (n=8) were treated with a GSI or a GSM at 30 mg/kg, p.o. Brain and plasma samples were collected at multiple time points and analyzed for their Aβ levels using ELISA and immunoblots. Similarly, Aβ levels from primary cortical neuronal cultures and Swedish APP over-expressing HEK293 cells were analyzed after treatment with the compounds mentioned above. The γ-secretase substrate, β-C terminal fragment (β-CTF), was detected by immunoblots. Treatment of rats with the GSI reduced Aβ in both the plasma and brain. The initial drop in plasma Aβ was followed by an “overshoot” that went beyond the basal levels whereas no Aβ overshoot was found in the brain. In the brain a transient accumulation of β-CTF were also detected. Similar accumulation of β-CTF was seen in primary cultured neurons and in APP over-expressing HEK293 cells treated with GSI, but not GSM. GSM inhibited plasma and brain Aβ in rats to levels comparable to those produced by GSI. However, neither Aβ overshoot in the plasma nor accumulation of β-CTF in the brain or cultured cells was detected. Our study shows that GSM, unlike GSI, does not cause an Aβ overshoot in the plasma. The lack of Aβ overshoot could be achieved by avoiding direct inhibition of γ-secretase and subsequent accumulation of β-CTF." @default.
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- W2080309385 date "2009-07-01" @default.
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- W2080309385 title "P3-269: γ-secretase inhibitor, but not modulator, causes Aβ overshoot and accumulation of β-CTF" @default.
- W2080309385 doi "https://doi.org/10.1016/j.jalz.2009.04.940" @default.
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