Jan 10, 2012

Piperidine acetic acid based γ-secretase modulators directly bind to Presenilin-1

ACS Chemical Neuroscience
Christina J CrumpYue-Ming Li


Aβ42 is believed to play a causative role in Alzheimer's disease (AD) pathogenesis. γ-Secretase modulators (GSMs) are actively being pursued as potential AD therapeutics because they selectively alter the cleavage site of the amyloid precursor protein (APP) to reduce the formation of Aβ42. However, the binding partner of acid based GSMs was unresolved until now. We have developed clickable photoaffinity probes based on piperidine acetic acid GSM-1 and identified PS1 as the target within the γ-secretase complex. Furthermore, we provide evidence that allosteric interaction of GSMs with PS1 results in a conformational change in the active site of the γ-secretase complex leading to the observed modulation of γ-secretase activity.

  • References35
  • Citations33


Mentioned in this Paper

Pathogenic Aspects
Amyloid Beta Precursor Protein Measurement
Cytokinesis of the Fertilized Ovum
Alzheimer's Disease
O-(glucuronic acid 2-sulfate)-(1--4)-O-(2,5)-anhydromannitol 6-sulfate

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