Stressed into generating amyloid-β

Cell Biology The enzyme γ-secretase cleaves amyloid precursor protein (APP) to generate amyloid-β, the aggregation of which is associated with Alzheimer's disease. However, clinical use of γ-secretase inhibitors is limited by disruption of the cleavage of other substrates. Jung et al. identified the protein SERP1 as an activator of γ-secretase under metabolic stress conditions that biased its cleavage activity toward APP. SERP1 knockdown in cells or mouse hippocampus decreased amyloid-β production. Blocking SERP1 may be more selective than γ-secretase inhibitors in reducing amyloid-β plaque accumulation. Sci. Signal. 13 , eaax8949 (2020).