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 Aß1-42, 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 Aß1-42 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.

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10 comments

  1. Have you heard about the product Prevagen? Prevagen’s active ingredient is apoaequorin which is a calcium-binding protein.

  2. Very nice analysis and insight regarding ER/SR Ca2+ levels – brought the 2 papers results together.

    brainhealthhacks.com

  3. There is a superb paper about Ca homeostasis, The Role of Chromogranins and Other Statins in Homeostasis: An Explanation of the Precise Regulation of Glucose and Ionised Calcium in the Blood; An Overview by Johan H. Koeslag; Peter T. Saunders

    Available through http://www.ingentaconnect.com/content/ben/cmciema/2004/00000004/00000003/art00011

    You can get a free copy of the paper from Koeslag via his web site at http://academic.sun.ac.za/medphys/articles.htm#a

    What’s interesting about all this is that amyloid plaque is also a major factor for diabetes and loss of pancreatic function…

  4. […] 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 […] […]

  5. […] Going with the flow: Calcium ion homeostasis and Alzheimer’s disease: Ouroboros highlights promising areas of Alzheimer´s research, specifically how "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 Alzheimer´s Disease". […]

  6. It’s great to see some good information about this disease and its cause. I remember reading a few years ago that they thought it was caused by eating to much red meat!

  7. Is there currently any research involving volunteers in the study of Alzheimer’s?

    Is there help for individuals in various stages of Alzheimer’s?

    What is known about the effects for individuals with Alzheimer’s? Are reversals of the damage done by this disease evident?

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