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.
摘要：
在动物模型的大脑中抑制环状AMP降解酶4型磷酸二酯酶（PDE4）在阿尔茨海默氏病（AD）中具有保护性。我们首次表明，来自PDE4D亚家族的酶不仅与AD小鼠模型中的β-淀粉样蛋白（Aβ）斑块共定位，而且Aβ直接与酶的催化机制相关。肽作图表明PDE4D是Aβ的优先PDE4亚家族,因为它具有独特的结合位点。有趣的是，向过表达PDE4D5长型的细胞外源添加Aβ导致PDE4活化和cAMP减少。我们提出了一种新的机制，其中PDE4长型可以被Aβ激活，导致cAMP信号传导减弱，促进AD认知功能丧失。
