Sin, Y. Y. et al. (2024) Beta-amyloid interacts with and activates the longform phosphodiesterase PDE4D5 in neuronal cells to reduce cAMP availability. FEBS Letters, (doi: 10.1002/1873-3468.14902) (PMID:38724485) (Early Online Publication)
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Abstract
Inhibition of the cyclic-AMP degrading enzyme phosphodiesterase type 4 (PDE4) in the brains of animal models is protective in Alzheimer's disease (AD). We show for the first time that enzymes from the subfamily PDE4D not only colocalize with beta-amyloid (Aβ) plaques in a mouse model of AD but that Aβ directly associates with the catalytic machinery of the enzyme. Peptide mapping suggests that PDE4D is the preferential PDE4 subfamily for Aβ as it possesses a unique binding site. Intriguingly, exogenous addition of Aβ to cells overexpressing the PDE4D5 longform caused PDE4 activation and a decrease in cAMP. We suggest a novel mechanism where PDE4 longforms can be activated by Aβ, resulting in the attenuation of cAMP signalling to promote loss of cognitive function in AD.
Item Type: | Articles |
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Additional Information: | This work was supported by a doctoral training studentship from the Biotechnology and Biological Sciences Research Council [grant number BB/F016735/1]. |
Keywords: | PDE4, Alzheimer’s disease, cyclic AMP, peptide array, beta amyloid. |
Status: | Early Online Publication |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Blair, Dr Connor and Wright, Tom and Baillie, Professor George and MacLeod, Miss Ruth and Cameron, Mr Ryan |
Authors: | Sin, Y. Y., Cameron, R. T., Schepers, M., MacLeod, R., Wright, T. A., Paes, D., van den Hove, D., Willems, E., Vanmierlo, T., Prickaerts, J., Blair, C. M., and Baillie, G. S. |
College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health |
Journal Name: | FEBS Letters |
Publisher: | Wiley |
ISSN: | 0014-5793 |
ISSN (Online): | 1873-3468 |
Published Online: | 09 May 2024 |
Copyright Holders: | Copyright © 2024 The Authors |
First Published: | First published in FEBS Letters 2024 |
Publisher Policy: | Reproduced under a Creative Commons License |
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