Palmeri Agostino, Ricciarelli Roberta, Gulisano Walter, Rivera Daniela, Rebosio Claudia, Calcagno Elisa, Tropea Maria Rosaria, Conti Silvia, Das Utpal, Roy Subhojit, Pronzato Maria Adelaide, Arancio Ottavio, Fedele Ernesto, Puzzo Daniela
Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, 95123 Catania, Italy.
Department of Experimental Medicine, Section of General Pathology, School of Medical and Pharmaceutical Sciences, University of Genoa, 16132 Genoa, Italy.
J Neurosci. 2017 Jul 19;37(29):6926-6937. doi: 10.1523/JNEUROSCI.3607-16.2017. Epub 2017 Jun 16.
High levels of amyloid-β peptide (Aβ) have been related to Alzheimer's disease pathogenesis. However, in the healthy brain, low physiologically relevant concentrations of Aβ are necessary for long-term potentiation (LTP) and memory. Because cGMP plays a key role in these processes, here we investigated whether the cyclic nucleotide cGMP influences Aβ levels and function during LTP and memory. We demonstrate that the increase of cGMP levels by the phosphodiesterase-5 inhibitors sildenafil and vardenafil induces a parallel release of Aβ due to a change in the approximation of amyloid precursor protein (APP) and the β-site APP cleaving enzyme 1. Moreover, electrophysiological and behavioral studies performed on animals of both sexes showed that blocking Aβ function, by using anti-murine Aβ antibodies or APP knock-out mice, prevents the cGMP-dependent enhancement of LTP and memory. Our data suggest that cGMP positively regulates Aβ levels in the healthy brain which, in turn, boosts synaptic plasticity and memory. Amyloid-β (Aβ) is a key pathogenetic factor in Alzheimer's disease. However, low concentrations of endogenous Aβ, mimicking levels of the peptide in the healthy brain, enhance hippocampal long-term potentiation (LTP) and memory. Because the second messenger cGMP exerts a central role in LTP mechanisms, here we studied whether cGMP affects Aβ levels and function during LTP. We show that cGMP enhances Aβ production by increasing the APP/BACE-1 convergence in endolysosomal compartments. Moreover, the cGMP-induced enhancement of LTP and memory was disrupted by blockade of Aβ, suggesting that the physiological effect of the cyclic nucleotide on LTP and memory is dependent upon Aβ.
高水平的β-淀粉样肽（Aβ）与阿尔茨海默病的发病机制有关。然而，在健康大脑中，低水平的具有生理相关性的Aβ浓度对于长时程增强（LTP）和记忆是必要的。由于环磷酸鸟苷（cGMP）在这些过程中起关键作用，因此我们在此研究了环核苷酸cGMP在LTP和记忆过程中是否会影响Aβ水平和功能。我们证明，磷酸二酯酶-5抑制剂西地那非和伐地那非使cGMP水平升高，由于淀粉样前体蛋白（APP）与β-位点APP裂解酶1的接近度发生变化，从而诱导Aβ平行释放。此外，对两性动物进行的电生理和行为研究表明，使用抗小鼠Aβ抗体或APP基因敲除小鼠阻断Aβ功能，可防止cGMP依赖性的LTP和记忆增强。我们的数据表明，cGMP在健康大脑中正向调节Aβ水平，进而促进突触可塑性和记忆。β-淀粉样肽（Aβ）是阿尔茨海默病的关键致病因素。然而，低浓度的内源性Aβ，模拟健康大脑中该肽的水平，可增强海马长时程增强（LTP）和记忆。由于第二信使cGMP在LTP机制中发挥核心作用，因此我们在此研究了cGMP在LTP过程中是否会影响Aβ水平和功能。我们发现，cGMP通过增加内溶酶体区室中APP/BACE-1的聚集来增强Aβ的产生。此外，Aβ阻断会破坏cGMP诱导的LTP和记忆增强，这表明环核苷酸对LTP和记忆的生理作用依赖于Aβ。
