The Calmodulin Hypothesis: Alzheimer’s Disease

O’Day, D.H., 2019. Alzheimer’s Disease: A short introduction to the calmodulin hypothesis.
AIMS Neuroscience, 6(4): 231–239.

Historically, Alzheimer’s disease (AD) has been characterized by the presence of extracellular amyloid beta (Ab) plaques and intracellular neurofibrillary tangles of phospho-tau (p-tau), two biomarkers that underlie neurodegeneration. It is likely, however, that earlier events involving the unregulated accumulation of calcium ions as well as other factors may be involved. O’Day and Myre presented the “Calmodulin Hypothesis” suggesting that calcium dysregulation would impact calmodulin the primary calcium-binding protein of all cells.

Figure 1. Some calmodulin binding proteins linked to events in Alzheimer’s disease. Putative and proven calmodulin binding proteins are indicated in purple. (O’Day & Myre, 2019).

They first showed that calmodulin regulated a large number of proteins involved in the formation of plaques and tangles. This was followed by evidence from various sources that specific receptors and channels as well as many AD risk factor proteins are CaM binding proteins. The extensive number of calmodulin-binding proteins linked to all aspects of AD strongly suggests not only that the “Calmodulin Hypothesis” has merit but also the current availability of FDA-approved calmodulin antagonists means AD research targeting calmodulin and its binding proteins could begin immediately.

Myre, Michael A., Robert J. Huber and Danton H. O’Day, 2018. Functional Analysis of Proteins Involved in Neurodegeneration Using the Model Organism Dictyostelium: Alzheimer’s, Huntington’s and Batten Disease. In: Molecular-Genetic and Statistical Techniques for Behavioral and Neural Research, Wim E. Crusio and Robert T. Gerlai (Eds), Elsevier.
Danton H. O’Day, Kristeen Eshak, and Michael A. Myre, 2015. Calmodulin Binding Proteins and Alzheimer’s Disease: A Review. Journal of Alzheimer’s Disease 46: 553-569.
Chavez SE, O’Day DH (2007) Calmodulin binds to and regulates the activity of beta-secretase (BACE1). Curr Res Alzheimers Dis 1: 37–47.
O’Day, Danton H.  and Michael A. Myre, 2008. Alzheimer’s Disease: The Calmodulin Connection and b-Amyloid. pp. 1-10. In “Alzheimer's Disease Research Trends”, pp. 1-10, Ed. A.P. Chan, Nova Biomedical, NY.
O’Day, Danton H. and Michael A. Myre, 2004. Calmodulin Binding Domains in Alzheimer’s Disease Proteins: Extending the Calcium Hypothesis. Biochemical Biophysical Research Communications 320: 1051-1054.