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C-terminal Fragment of Presenilin Is the Molecular Target of a Dipeptidic γ-Secretase-specific Inhibitor DAPT (N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-Butyl Ester)*
TLDR
It is shown that one of the major γ-secretase inhibitors of dipeptidic type, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT), targets the C-terminal fragment of PS by designing and synthesizing DAP-BpB, a photoactivable DAPT derivative. Expand
Activity-Dependent Proteolytic Cleavage of Neuroligin-1
TLDR
It is reported that neuroligin-1 (NLG1) undergoes ectodomain shedding at the juxtamembrane stalk region to generate a secreted form of NLG1 and a membrane-tethered C-terminal fragment (CTF) in adult rat brains in vivo as well as in neuronal cultures. Expand
Sulindac Sulfide Is a Noncompetitive γ-Secretase Inhibitor That Preferentially Reduces Aβ42 Generation*
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been known to reduce risk for Alzheimer's disease. In addition to the anti-inflammatory effects of NSAIDs to block cylooxygenase, it has been shownExpand
BACE1 Activity Is Modulated by Cell-Associated Sphingosine-1-Phosphate
TLDR
It is shown that the activity of β-site APP cleaving enzyme-1 (BACE1), the rate-limiting enzyme for amyloid-β peptide production, is modulated by S1P in mouse neurons, suggesting that cellular S1p directly modulates BACE1 activity. Expand
Sulindac sulfide is a noncompetitive gamma-secretase inhibitor that preferentially reduces Abeta 42 generation.
TLDR
It is shown that sulindac sulfide (SSide) directly acts on gamma- secretase and preferentially inhibits the gamma(42)-secretase activity derived from the 3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonate-solubilized membrane fractions of HeLa cells, in an in vitro gamma-secretase assay. Expand
BACE1 activity is modulated by cell-associated sphingosine-1-phosphate
heimer’s disease since it participates in the generation of the toxic amyloid ß-peptide (Aß) from the amyloid precursor protein (APP). g-Secretase is a membrane bound protein complex consisting ofExpand
Total synthesis of ecteinascidin 743.
The total synthesis of ecteinascidin 743 (1), an extremely potent antitumor agent, has been accomplished. The synthesis features Ugi's 4CC reaction, intramolecular Heck reaction, phenol-aldehydeExpand
Divergent synthesis of multifunctional molecular probes to elucidate the enzyme specificity of dipeptidic gamma-secretase inhibitors.
TLDR
The divergent synthesis of molecular probes has been successfully applied to characterize the interaction of GSIs with their molecular targets and define the structural requirements for inhibitor binding to intramembrane-cleaving proteases. Expand
Allosteric regulation of γ-secretase activity by a phenylimidazole-type γ-secretase modulator
TLDR
A model for the mechanism of action of the phenylimidazole-type GSM in which binding at the luminal side of PS induces a conformational change in the catalytic center of γ-secretase to modulate Aβ production is provided. Expand
BIN1 regulates BACE1 intracellular trafficking and amyloid-β production.
TLDR
It is reported that the depletion of BIN1 increases cellular BACE1 levels through impaired endosomal trafficking and reduces Bace1 lysosomal degradation, resulting in increased Aβ production. Expand
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