摘要：SummaryA change in Presenilin (PS)/γ-secretase activity is linked to essential biological events as well as to the progression of many diseases. However, not much is known about how PS/γ-secretase activity is spatiotemporally regulated in cells. One of the limitations is lack of tools to directly monitor dynamic behavior of the PS/γ-secretase in intact/live cells. Here we present successful development and validation of the Förster resonance energy transfer (FRET)-based biosensors that enable quantitative monitoring of endogenous PS/γ-secretase activity in live cells longitudinally on a cell-by-cell basis. Using these FRET biosensors, we uncovered that PS/γ-secretase activity is heterogeneously regulated among live neurons.Graphical AbstractDisplay OmittedHighlights•C99 R-G biosensor reports endogenous PS/γ-secretase activity in live cells•Modified donor/acceptor and linker length result in higher sensitivity C99 Y-T sensor(s)•APP C99 in the C99 Y-T biosensor can be replaced with Notch1 N100•PS/γ-secretase activity is heterogeneously regulated among live neuronsBiological Sciences; Cell Biology; Methodology in Biological Sciences; Neuroscience
