Nicastrin binds other γ-secretase components when it is not binding Rer1p (right).

Alzheimer's disease might be slowed by inhibiting γ-secretase, the membrane protease complex that cleaves amyloid precursor protein (APP). Spasic et al. (page 629) now identify an endogenous inhibitor that prevents γ-secretase complex assembly and activity and thus might be targeted for therapy.

APP cleavage by γ-secretase leads to amyloid plaque deposition, one possible cause of Alzheimer's symptoms. γ-secretase is composed of four proteins—presenilin, nicastrin, PEN-2, and APH-1—which must come together for cleavage activity.

Although all four components are present in the ER, their assembly into functional γ-secretase is somehow restricted; most of the active enzyme is found close to the cell surface. Assembly of γ-secretase begins with the binding of nicastrin to APH-1. This binding, Spasic and colleagues now find, is prevented early in the secretion pathway by Rer1p, a membrane receptor that retrieves proteins from the Golgi back to the ER. Rer1p binds to nicastrin, thus interfering with nicastrin's ability to bind APH-1. Decreasing the amount of Rer1p led to an increase in γ-secretase activity.

Exactly what triggers Rer1p to release nicastrin and allow it to bind to APH-1, and subsequently to the other γ-secretase components, remains to be determined. Preventing this release might provide a means to reduce γ-secretase activity and thus amyloid plaque formation.