Going with the flow: Calcium ion homeostasis and Alzheimer’s disease

Two related findings that surely signal a major new direction in the study of Alzheimer’s disease (AD): Two means of controlling intracellular calcium homeostasis appears to play a major role in controlling levels of the Aß protein, a major component of the senile plaques that characterize AD and (thusly) a likely source of AD-associated cell death.

Specifically, deficiencies in two distinct calcium pumps appear to promote molecular events associated with AD pathology. Green et al. report that SERCA, which pumps excess Ca2+ into the endoplasmic reticulum (ER) or its muscle equivalent, the sarcoplasmic reticulum (SR), has diminished activity in cells lacking presenilin-1 and presenilin-2 (PS1/PS2 deficiencies are associated at the cellular level with increased production of the proteotoxic peptide Aß_1-42, and at the organismal level with increased risk of early-onset AD). Critically, modulation of SERCA activity on its own can affect the rate of Aß synthesis. Taken together, the data argue that PS1/PS2 regulate intracellular Ca2+, and that calcium in turn influences production of Aß (and thereby the risk and progression of AD).

Meanwhile, Dreses-Werringloer et al. have identified CALHM1, a calcium pump on the plasma membrane (as opposed to the ER/SR membrane) that is also involved in Aß production. A naturally occurring polymorphism in the CALHM1 gene is strongly associated with AD; the authors propose that the mutation interferes with Ca2+ permeability and that this alters Aß expression via an as-yet-undetermined mechanism.

The two stories are similar, but the attentive reader will notice a curious feature: The calcium is moving in opposite directions. SERCA pumps Ca2+ out of the cytosol into the ER/SR, so a deficiency in SERCA would increase cytosolic Ca2+ (and, incidentally, the ratio of cytosolic vs. ER/SR Ca2+). In contrast, CALHM1 pumps Ca2+ into the cytosol, so that a deficiency in that protein would decrease cytosolic Ca2+. But deficiencies in either gene promote AD (or at least AD-related molecular pathology).

What gives? It’s possible that the (similar) effects on Aß levels are mediated by totally different mechanisms, but I’m more enticed by another idea. Suppose that ER/SR Ca2+ levels are key to Aß production, with decreased ER/SR calcium reserves associated with either higher Aß expression or greater production/secretion of Aß_1-42 in particular. In both mutants, ER/SR calcium reserves would be depleted: In the case of SERCA, because there’s no pump transferring cytosolic Ca2+ into the ER/SR, but in the case of CALHM1, because there’s no pump transferring extracellularCa2+ into the cytosol, whence it could be subsequently pumped into the ER/SR. Aß is after all a secreted protein, so the ion concentrations in the compartments of the secretory pathway could conceivably be crucial to the production of amyloid protein.