%0 Journal Article
%T Beta-amyloid interacts with and activates the long-form phosphodiesterase PDE4D5 in neuronal cells to reduce cAMP availability.
%A Sin YY
%A Cameron RT
%A Schepers M
%A MacLeod R
%A Wright TA
%A Paes D
%A van den Hove D
%A Willems E
%A Vanmierlo T
%A Prickaerts J
%A Blair CM
%A Baillie GS
%J FEBS Lett
%V 598
%N 13
%D 2024 Jul 9
%M 38724485
%F 3.864
%R 10.1002/1873-3468.14902
%X 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.