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. 2023 Jan 11;24(2):1393.
doi: 10.3390/ijms24021393.

Calmodulin and Amyloid Beta as Coregulators of Critical Events during the Onset and Progression of Alzheimer's Disease

Danton H O'Day  1   2
Affiliations

Calmodulin and Amyloid Beta as Coregulators of Critical Events during the Onset and Progression of Alzheimer's Disease

Danton H O'Day. Int J Mol Sci. .

Abstract

Calmodulin (CaM) and a diversity of CaM-binding proteins (CaMBPs) are involved in the onset and progression of Alzheimer's disease (AD). In the amyloidogenic pathway, AβPP1, 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 (Aβ) and oligomers (Aβo). The recent revelations that Aβ and Aβo each bind to both CaM and to a host of Aβ receptors that are also CaMBPs adds a new level of complexity to our understanding of the onset and progression of AD. Multiple Aβ 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 Aβ receptors are AD risk factors while still others are involved in the amyloidogenic pathway. Aβ binding to receptors not only serves to control CaM's ability to regulate critical proteins, but it is also implicated in Aβ turnover. The complexity of the Aβ/CaM/CaMBP interactions is analyzed using two events: Aβ generation and NMDAR function. The interactions between Aβ, 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.

Keywords: Alzheimer’s disease; NMDAR; amyloid beta receptors; amyloid pathway; calcium regulation; calmodulin binding proteins; neurodegeneration.

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Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
Experimentally validated calmodulin binding proteins (CaMBPs, Green) are involved in critical events in the onset and progression of Alzheimer’s disease.
Figure 2
Figure 2
The interplay between calmodulin (CaM) and amyloid beta (Aβ) in the amyloid pathway. Calmodulin (CaM) and its binding proteins that bind to Aβ are shown in green.
Figure 3
Figure 3
Some types of regulation open to Aβ receptors that are calmodulin binding proteins. pReceptor = phosphorylated receptor. See text for details.
See this image and copyright information in PMC

References

    1. Karen E., DeStrooper B. The amyloid hypothesis in Alzheimer disease: New insights from new therapeutics. Nature. 2022;21:306–318. doi: 10.1038/s41573-022-00391-w. - DOI - PubMed
    1. Khachaturian Z.S. Towards theories of brain aging. In: Kay D.S., Burrows G.W., editors. Handbook of Studies on Psychiatry and Old Age. Elsevier Science Publishers, B.V.; Amsterdam, The Netherlands: 1984. pp. 7–30.
    1. Khachaturian Z.S. Calcium hypothesis of Alzheimer’s disease and brain aging. Ann. N. Y. Acad. Sci. 1994;747:1–11. doi: 10.1111/j.1749-6632.1994.tb44398.x. - DOI - PubMed
    1. Hampel H., Caraci F., Cuello A.C., Caruso G., Nisticò R., Corbo M., Baldacci F., Toschi N., Garaci F., Chiesa P.A., et al. A Path toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer’s Disease. Front. Immunol. 2020;11:456. doi: 10.3389/fimmu.2020.00456. - DOI - PMC - PubMed
    1. Gulisano W., Maugeri D., Baltrons M.A., Fà M., Amato A., Palmeri A., D’adamio L., Grassi C., Devanand D., Honig L.S., et al. Role of amyloid-β and tau proteins in Alzheimer’s disease: Confuting the amyloid cascade. J. Alzheimer’s Dis. 2018;64:S611–S631. doi: 10.3233/JAD-179935. - DOI - PMC - PubMed

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