ST101 induces a novel 17 kDa APP cleavage that precludes Aβ generation in vivo
Kim N Green1, Hasan Khashwji, Tatiana Estrada
1From the Department of Neurobiology and Behavior Institute for Memory Impairments and Neurological Disorders, University of California at Irvine, Irvine, CA 92697-4545, USA. kngreen@uci.edu
Objective:
Inhibiting Aβ generation is a prime therapeutic goal for preventing or treating Alzheimer disease. Here we sought to identify any disease-modifying properties of an azaindolizinone derivative, spiro[imidazo[1,2-a]pyridine-3,2-idan]-2(3H)-one (ST101 or ZSET1446).
Methods:
The effects of ST101 were studied in 3xTg-AD mice and young cynomolgus monkeys using a combination of biochemical and histological analyses.
Results:
Here we describe that ST101 induces cleavage of APP protein at a novel site, generating a 17 kDa C-terminal fragment. This 17 kDa APP cleavage product does not appear to be a substrate for either α- or β-secretase, and thus bypasses generation of Aβ. ST101 is orally active, efficacious at low doses, improves memory function, and robustly reduces brain Aβ in transgenic mice and nonhuman primates.
Interpretation:
Using rodent and nonhuman primate models, we show that ST101 represents a novel class of small molecules that reduce central nervous system levels of Aβ by inducing an alternate pathway of APP cleavage.
