Retromers are multiprotein complexes responsible for trafficking cargo out of endosomes. This is an important function that, in the case of amyloid-precursor protein (APP), is neuroprotective by preventing APP from being cleaved into Alzheimer’s disease-inducing fragments via the endosome. TPT-260 is a thiophene thiourea derivative that acts as a chaperone to stabilize the retromer complex against thermal denaturation (Kd = ~5 μM). In cultured hippocampal neurons, TPT-260 dose-dependently increases the level of retromer proteins, redirects APP from the endosome, and reduces the formation of pathogenic APP.
