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).

Since then, extensive research has supported O’Day and Myre’s Calmodulin Hypothesis. 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. Here are summaries from four recent papers.

O’Day, Danton H. and Robert J. Huber, 2022. Calmodulin binding proteins and neuroinflammation in multiple neurodegenerative diseases. BMC Neuroscience 23: 10.

At least 24 critical proteins involved in neuroinflammation are putative or proven calmodulin binding proteins. Eleven neuroinflammatory proteins (TREM2, CD33, PILRA, CR1, MS4A, CLU, ABCA7, EPHA1, ABCA1, CH3L1/YKL-40 and NLRP3) possess at least one binding domain within which valid binding motifs are present. Previous research identified 13 more neuroinflammation linked putative calmodulin binding proteins (BACE1, BIN1, CaMKII, PP2B, PMCA, NOS, NMDAR, AchR, Ado A2AR, Ab, APOE, SNCA, TMEM175). Many of which are linked to multiple neurodegenerative diseases. Calmodulin binding proteins lie at the heart of neuroinflammatory events associated with multiple neurodegenerative diseases. Many calmodulin-based pharmaceuticals have been successfully used to treat Huntington’s and other neurodegenerative diseases arguing for their immediate therapeutic implementation.

O’Day, Danton H., 2022. Calmodulin binding domains in critical risk proteins involved in neurodegeneration. Current Issues in Molecular Biology 44: 5802-5814.

The intimate and entangled relationship between calmodulin binding proteins and all phases of Alzheimer’s disease has been established but the relationship to other neurodegenerative diseases is just being evaluated. Risk factors and hallmark proteins from PD (SNCA, Parkin, PINK1, LRRK2, PARK7), HD (Htt, TGM1, TGM2), LBD (TMEM175, GBA), and ALS/FTD (VCP, FUS, TDP-43, TBK1, C90rf72, SQSTM1, CHCHD10, SOD1) were scanned for the presence of calmodulin binding domains and, within them, appropriate binding motifs. Binding domains and motifs identified in risk proteins involved in HD, PD, LBD and ALS/FTD coupled with other studies on proven calmodulin binding proteins supports the central and potentially critical role for calmodulin in neurodegenerative events.

O’Day, Danton H., 2023. Calmodulin and amyloid beta as coregulators of critical events during the onset and progression of Alzheimer’s disease.  International Journal of Molecular Sciences 24: 1393-1401.

In the amyloidogenic pathway, AbPP1, BACE1 and PSEN-1 are all calcium-dependent CaMBPs as are the risk factor proteins BIN1 and TREM2. Ca2+/CaM-dependent protein kinase II (CaMKII) and calcineurin (CaN) are classic CaMBPs involved in memory and plasticity, two events impacted by AD. Coupled with these events is the production of amyloid beta monomers (Ab) and oligomers (Abo). Ab and Abo each bind to both CaM and to a host of Ab receptors that are also CaMBPs adding a new level of complexity to our understanding of AD. Multiple Ab receptors that are proven CaMBPs (e.g., NMDAR, PMCA) are involved in calcium homeostasis an early event in AD and other neurodegenerative diseases. Other CaMBPs that are Ab receptors are AD risk factors while still others are involved in the amyloidogenic pathway.  Ab binding to receptors not only serves to control CaM’s ability to regulate critical proteins, but it is also implicated in Ab turnover. The complexity of the Ab/CaM/CaMBP interactions is analyzed using two events: Ab generation and NMDAR function. The interactions between Ab, CaM and CaMBPs reveals a new level of complexity to critical events associated with the onset and progression of AD and may help to explain the failure to develop successful therapeutic treatments for the disease.

O’Day, Danton H., 2023. Phytochemical Interactions with Calmodulin and Critical Calmodulin Binding Proteins Involved in Amyloidogenesis in Alzheimer’s Disease. Biomolecules 13, 678.

An increasing number of plant-based herbal treatments, dietary supplements, medical foods and nutraceuticals and their component phytochemicals are used as alternative treatments to prevent or slow the onset and progression of Alzheimer’s disease. Their appeal stems from the fact that no current pharmaceutical or medical treatment can accomplish this. While a handful of pharmaceuticals are approved to treat Alzheimer’s, none has been shown to prevent, significantly slow or stop the disease. As a result, many see the appeal of alternative plant-based treatments as an option. Here, we show that many phytochemicals proposed or used as Alzheimer’s treatments share a common theme: they work via a calmodulin-mediated mode of action. Some phytochemicals bind to and inhibit calmodulin directly while others bind to and regulate calmodulin-binding proteins, including Aβ monomers and BACE1. Phytochemical binding to Aβ monomers can prevent the formation of Aβ oligomers. A limited number of phytochemicals are also known to stimulate calmodulin gene expression. The significance of these interactions to amyloidogenesis in Alzheimer’s disease is reviewed.

Updated 11June2023