Inhaltszusammenfassung

The intramembrane-cleaving protease gamma-secretase catalyzes the last step in the generation of toxic amyloid-beta (A beta) peptides and is a principal therapeutic target in Alzheimer's disease. Both preclinical and clinical studies have demonstrated that inhibition of gamma-secretase is associated with prohibitive side effects due to suppression of Notch processing and signaling. Potentially safer are gamma-secretase modulators (GSMs), which are small molecules that selectively lower genera...The intramembrane-cleaving protease gamma-secretase catalyzes the last step in the generation of toxic amyloid-beta (A beta) peptides and is a principal therapeutic target in Alzheimer's disease. Both preclinical and clinical studies have demonstrated that inhibition of gamma-secretase is associated with prohibitive side effects due to suppression of Notch processing and signaling. Potentially safer are gamma-secretase modulators (GSMs), which are small molecules that selectively lower generation of the highly amyloidogenic A beta 42 peptides but spare Notch processing. GSMs with nanomolar potency and favorable pharmacological properties have been described, but the molecular mechanism of GSMs remains uncertain and both the substrate amyloid precursor protein (APP) and subunits of the gamma-secretase complex have been proposed as the molecular target of GSMs. We have generated a potent photo-probe based on an acidic GSM that lowers A beta 42 generation with an IC50 of 290 nM in cellular assays. By combining in vivo photo-crosslinking with affinity purification, we demonstrated that this probe binds the N-terminal fragment of presenilin (PSEN), the catalytic subunit of the gamma-secretase complex, in living cells. Labeling was not observed for APP or any of the other gamma-secretase subunits. Binding was readily competed by structurally divergent acidic and non-acidic GSMs suggesting a shared mode of action. These findings indicate that potent acidic GSMs target presenilin to modulate the enzymatic activity of the gamma-secretase complex.» weiterlesen» einklappen

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DDC Sachgruppe:
Medizin