Inhibition of PDE2 reverses beta amyloid induced memory impairment through regulation of PKA/PKG-dependent neuro-inflammatory and apoptotic pathways

Wang, Li; Xiaokaiti, Yilixiati; Wang, Gang; Xu, Xiaoxiao; Chen, Ling; Huang, Xianfeng; Liu, Li; Pan, Jianchun; Hu, Shuqun; Chen, Zhuoyou; Xu, Ying

doi:10.1038/s41598-017-08070-2

Cited by 31 publications

(22 citation statements)

References 41 publications

(41 reference statements)

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“…Our previous studies suggested that microinjection of Aβ into the CA1 induced decreased second messengers (cAMP and cGMP) in the hippocampus (Wang L. et al, 2017 ). As the enzymes that hydrolyze and inactivate the second messenger cAMP, PDE4 is found to be associated with memory regulation.…”

Section: Discussionmentioning

confidence: 97%

Inhibition of Phosphodiesterase-4 Reverses Aβ-Induced Memory Impairment by Regulation of HPA Axis Related cAMP Signaling

Zhu

et al. 2018

Front. Aging Neurosci.

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Beta amyloid peptides (Aβ) are found to be associated with dysfunction of hypothalamic-pituitary-adrenal axis (HPA axis) that leads to memory and cognitive deficits in patients with Alzheimer's disease (AD). Phosphodiesterase 4 (PDE4) inhibitors increase the intracellular cAMP activities, which may ameliorate cognitive deficits associated with AD. However, it remains unclear whether PDE4-mediated reversal of cognitive impairment in mouse model of AD is related to HPA axis and downstream cAMP-dependent pathway. The present study investigated the effects of PDE4 inhibitor rolipram on Aβ1-42-induced cognitive dysfunction and its underlying mechanisms. The step-down passive avoidance (PA) and Morris water-maze (MWM) tests were conducted 1 week (1 W), 2 months (2 M), and 6 months (6 M) after intracerebroventricular microjection (i.c.v.) of Aβ1-42. The results suggested that memory impairment emerged as early as 1 W, peaked at 2 M, and lasted until 6 M after injection. Chronic treatment with rolipram (0.1, 0.5, 1.0 mg/kg/d, i.p.) for 2 weeks (i.e., treatment started at 1.5 months after Aβ1-42 microinjection) dose-dependently improved memory performance in both MWM and PA tests. Moreover, rolipram reversed the Aβ-induced increases in serum corticosterone (CORT), corticotropin-releasing factor, and glucocorticoid receptors (CRF-R and GR) levels, whereas it decreases in brain-derived neurotropic factor (BDNF) and the ratio of pCREB to CREB expression. These effects of rolipram were prevented by pre-treatment with PKA inhibitor H89. The findings indicated that the protective effects of rolipram against Aβ1-42-induced memory deficits might involve HPA axis and cAMP-CREB-BDNF signaling.

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Section: Discussionmentioning

confidence: 97%

Inhibition of Phosphodiesterase-4 Reverses Aβ-Induced Memory Impairment by Regulation of HPA Axis Related cAMP Signaling

Zhu

et al. 2018

Front. Aging Neurosci.

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“…MAPK8IP2 is also known as JIP2, c-Jun NH(2)-terminal kinase (JNK)-interacting protein 2, which is known to interact with Aβ to play an important role in the metabolism and/or the function of Aβ including the regulation of Aβ phosphorylation by JNK [38]. Inhibition of PDE2 has been shown to rescue Aβ induced memory impairment via regulation of PKA/ PKG-dependent neuroinflammatory and apoptotic pathways [39]. Finally, genetic variants from BZRAP1-AS1 were previously implicated to be associated with AD [40].…”

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confidence: 99%

Epigenome-wide association study of Alzheimer’s disease replicates 22 differentially methylated positions and 30 differentially methylated regions

Sun

Wang

2020

Clin Epigenet

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Background Growing evidence shows that epigenetic modifications play a role in Alzheimer’s disease (AD). We performed an epigenome-wide association study (EWAS) to evaluate the DNA methylation differences using postmortem superior temporal gyrus (STG) and inferior frontal gyrus (IFG) samples. Results Samples from 72 AD patients and 62 age-matched cognitively normal controls were assayed using Illumina© Infinium MethylationEPIC BeadChip. Five and 14 differentially methylated positions (DMPs) associated with pathology (i.e., Braak stage) with p value less than Bonferroni correction threshold of 6.79 × 10–8 in the STG and IFG were identified, respectively. These cytosine–phosphate–guanine (CpG) sites included promoter associated cg26263477 annotated to ABCA7 in the STG (p = 1.21 × 10–11), and cg14058329 annotated to the HOXA5/HOXA3/HOXA-AS3 gene cluster (p = 1.62 × 10–9) and cg09448088 (p = 3.95 × 10–9) annotated to MCF2L in the IFG. These genes were previously reported to harbor DMPs and/or differentially methylated regions (DMRs). Previously reported DMPs annotated to RMGA, GNG7, HOXA3, GPR56, SPG7, PCNT, RP11-961A15.1, MCF2L, RHBDF2, ANK1, PCNT, TPRG1, and RASGEF1C were replicated (p < 0.0001). One hundred twenty-one and 173 DMRs associated with pathology in the STG and IFG, respectively, were additionally identified. Of these, DMRs annotated to 30 unique genes were also identified as significant DMRs in the same brain region in a recent meta-analysis, while additional DMRs annotated to 12 genes were reported as DMRs in a different brain region or in a cross-cortex meta-analysis. The significant DMRs were enriched in promoters, CpG islands, and exons in the genome. Gene set enrichment analysis of DMPs and DMRs showed that gene sets involved in neuroinflammation (e.g., microglia differentiation), neurogenesis, and cognition were enriched (false discovery rate (FDR) < 0.05). Conclusions Twenty-two DMPs and 30 DMRs associated with pathology were replicated, and novel DMPs and DMRs were discovered.

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“…In addition to PDE9 inhibitors, other PDE inhibitors also affect LTP-related plasticity (Heckman et al, 2015; Puzzo et al, 2008; Reneerkens et al, 2009). Specific inhibitors of PDE1 (Snyder et al, 2016), PDE2 (Boess et al, 2004; Wang et al, 2017), PDE3 (Hiramatsu et al, 2010), PDE4 (Bruno et al, 2011; Ricciarelli et al, 2017), PDE5 (Prickaerts et al, 1997; Prickaerts et al, 2002b), PDE7 (Perez-Gonzalez et al, 2013), and PDE9 (Hutson et al, 2011; van der Staay et al, 2008) have been shown to enhance memory performance in rodent. For example, the selective PDE2 inhibitor BAY 60-7550 improves memory acquisition and consolidation in the object recognition task (Boess et al, 2004; Domek-Lopacinska et al, 2008; Rutten et al, 2007), and reverses the deficit in object recognition produced by acute tryptophan depletion (van Donkelaar et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

The Phosphodiesterase 9 Inhibitor PF‐04449613 Promotes Dendritic Spine Formation and Performance Improvement after Motor Learning

Lai

et al. 2018

Developmental Neurobiology

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The cyclic nucleotide cGMP is an intracellular second messenger with important roles in neuronal functions and animals' behaviors. The phosphodiesterases (PDEs) are a family of enzymes that hydrolyze the second messengers cGMP and cAMP. Inhibition of phosphodiesterase 9 (PDE9), a main isoform of PDEs hydrolyzing cGMP, has been shown to improve learning and memory as well as cognitive function in rodents. However, the role of PDE9 in regulating neuronal structure and function in vivo remains unclear. Here we used in vivo two-photon microscopy to investigate the effect of a selective PDE9 inhibitor PF-04449613 on the activity and plasticity of dendritic spines of layer V pyramidal neurons in the mouse primary motor cortex. We found that administration of PF-04449613 increased calcium activity of dendrites and dendritic spines of layer V pyramidal neurons in mice under resting and running conditions. Chronic treatment of PF-04449613 over weeks increased dendritic spine formation and elimination under basal conditions. Furthermore, PF-04449613 treatment over 1-7 days increased the formation and survival of new spines as well as performance improvement after rotarod motor training. Taken together, our studies suggest that elevating the level of cGMP with the PDE9 inhibitor PF-04449613 increases synaptic calcium activity and learning-dependent synaptic plasticity, thereby contributing to performance improvement after learning. © 2018 Wiley Periodicals, Inc. Develop Neurobiol 00: 000-000, 2018.

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Inhibition of PDE2 reverses beta amyloid induced memory impairment through regulation of PKA/PKG-dependent neuro-inflammatory and apoptotic pathways

Cited by 31 publications

References 41 publications

Inhibition of Phosphodiesterase-4 Reverses Aβ-Induced Memory Impairment by Regulation of HPA Axis Related cAMP Signaling

Inhibition of Phosphodiesterase-4 Reverses Aβ-Induced Memory Impairment by Regulation of HPA Axis Related cAMP Signaling

Epigenome-wide association study of Alzheimer’s disease replicates 22 differentially methylated positions and 30 differentially methylated regions

The Phosphodiesterase 9 Inhibitor PF‐04449613 Promotes Dendritic Spine Formation and Performance Improvement after Motor Learning

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