Daniel Hong Seng Lee

γ-secretase inhibitors (GSIs) have been developed to reduce amyloid-β (Aβ) production for the treatment of Alzheimer's disease by inhibiting the cleavage of amyloid precursor protein (APP). However, cross-inhibitory activity on the processing of Notch can cause adverse reactions. To avoid these undesirable effects, γ-secretase modulators (GSMs) are being developed to selectively reduce toxic Aβ production without perturbing Notch signaling. As it is also known that GSIs can cause a paradoxical increase of plasma Aβ over the baseline after a transient reduction (known as Aβ-rebound), we asked if GSMs would cause a similar rebound and what the potential mechanism might be. Our studies were performed with one GSI (LY-450139) and two chemically distinct GSMs. Although LY-450139 caused Aβ-rebound as expected in rat plasma, the two GSMs did not. Inhibition of APP processing by LY-450139 induced an accumulation of γ-secretase substrates, α- and β-C-terminal fragments of APP, but neither GSM caused such an accumulation. In conclusion, we discover that GSMs, unlike GSIs, do not cause Aβ-rebound, possibly because of the lack of accumulation of β-C-terminal fragments. GSMs may be superior to GSIs in the treatment of Alzheimer's disease not only by sparing Notch signaling but also by avoiding Aβ-rebound.

Abstract A comparison of human adult and fetal adrenals with respect to their levels of glyceryl ether lipids and other lipid components is reported. Fetal glands contained significantly lower levels of alk‐1‐enyl phosphoglycerides and of cholesterol. Neutral glyceryl ether diesters, and ethanolamine and choline phosphoglycerides were isolated from adult adrenal tissue. The composition of the O ‐alkyl glycerol groups in these lipid fractions was obtained by means of gas chromatography of the trimethylsilyl ethers and diacetyl derivatives; O ‐alk‐1‐enyl glycerols were analyzed as their diacetates. About one‐half of the alkyl and alk‐1‐enyl glycerol moieties present in glyceryl ether diesters contained hydrocarbon side chains with 20, 22, or 24 carbon atoms. Long hydrocarbon chains (C 19–24 ) were also found in the O ‐alkyl glycerol moieties present in the total lipids of fetal adrenals.