Presenilin (red) and SERCA (green) cozy up in this fibroblast.

Two enzymes that help manufacture amyloid β, the protein that accumulates in the brain in Alzheimer's disease, also take on another job. As Green et al. report, the enzymes, known as presenilins, help set calcium levels inside cells by activating a pump protein.

Presenilins partner with other proteins to create the enzyme γ-secretase, which helps snip amyloid β into shape. Faulty presenilins trigger a rare, early-onset variant of Alzheimer's disease (AD) that strikes patients who are under 65 yr old. Presenilins might also help dictate how much calcium enters and exits the ER, which serves as the cell's storehouse for the ion. For instance, ER calcium release skyrockets in cells from patients with early onset AD. And in cells lacking one of the presenilins, the ER contains less calcium than normal. These results suggest that the presenilins help regulate SERCA, the protein that pumps calcium into storage.

To test that possibility, Green et al. eliminated both presenilins from cells and found that their cytoplasmic calcium levels were higher than normal. The scientists also measured how rapidly frog eggs shuttled a controlled influx of calcium ions into the ER. Engineering the eggs to manufacture presenilins, which they don't normally make, accelerated calcium pumping into the ER.

The location of presenilins and SERCA reflects their close relationship, the team found. Presenilins not only settle alongside SERCA in the ER, they attach to the pump protein. Green et al. also discovered a link between amyloid β and SERCA: increased SERCA activity translated into higher amyloid β production. SERCA might exert this effect by prodding γ-secretase, the team concludes.

The results show that along with forming part of the protein-slicing γ-secretase complex, presenilins are crucial for regulating intracellular calcium homeostasis. Both functions allow the enzymes to exert control over amyloid β formation.

Green, K.N., et al.
J. Cell Biol.