Phosphodiesterase 4D Gene Modifies the Functional Network of Patients With Mild Cognitive Impairment and Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is affected by several genetic variants. It has been demonstrated that genetic variants affect brain organization and function. In this study, using whole genome-wide association studies (GWAS), we analyzed the functional magnetic resonance imaging and genetic data from the Alzheimer's Disease Neuroimaging Initiative dataset (ADNI) dataset and identified genetic variants associated with the topology of the functional brain network http://www. adni-info.org. We found three novel loci (rs2409627, rs9647533, and rs11955845) in an intron of the phosphodiesterase 4D (PDE4D) gene that contribute to abnormalities in the topological organization of the functional network. In particular, compared to the wildtype genotype, the subjects carrying the PDE4D variants had altered network properties, including a significantly reduced clustering coefficient, small-worldness, global and local efficiency, a significantly enhanced path length and a normalized path length. In addition, we found that all global brain network attributes were affected by PDE4D variants to different extents as the disease progressed. Additionally, brain regions with alterations in nodal efficiency due to the variations in PDE4D were predominant in the limbic lobe, temporal lobe and frontal lobes. PDE4D has a great effect on memory consolidation and cognition through long-term potentiation (LTP) effects and/or the promotion of inflammatory effects. PDE4D variants might be a main reasons underlyling for the abnormal topological properties and cognitive impairment. Furthermore, we speculated that PDE4D is a risk factor for neural degenerative diseases and provided important clues for the earlier detection and therapeutic intervention for AD.

Selective PDE4 subtype inhibition provides new opportunities to intervene in neuroinflammatory versus myelin damaging hallmarks of multiple sclerosis

“…On the contrary, the PDE4D-sparing PDE4 inhibitor ABI-4 did not affect inflammatory processes in murine microglia cultures, excluding a direct role for PDE4D in inflammation (Hedde et al, 2017). Alternatively, PDE4D-specific inhibition has been largely related to improved memory and neuroplasticity (Mohammadnejad et al, 2021;Xiang et al, 2020;Zhang et al, 2017;Shi et al, 2021;Zhang et al, 2014;Sierksma et al, 2014;Cui et al, 2019). However, despite being a therapeutic target, it is hypothesized that especially PDE4D is responsible for the emetic side effects upon pan PDE4 inhibition since PDE4D is highly expressed in the area postrema, the chemoreceptor trigger zone for emesis in the brainstem, compared to other PDE4 genes (Mori et al, 2010).…”

Systematic Analysis of Biological Processes Reveals Gene Co-expression Modules Driving Pathway Dysregulation in Alzheimer’s Disease

“…A hub gene identified in EXC-M2, PDE4D, has been previously shown to result in abnormalities in the topological organization of functional brain networks (85). As a phosphodiesterase, PDE4D plays a pivotal role in regulating cAMP dynamics in neurons and glial cells (86), which ultimately influence memory formation and neuroinflammation (85,87). We noted GAP43, expressed in EXC-M3, whose elevated expression is recognized as a marker for tau and amyloid-driven pathologies.…”

The Repertoire of Small-Molecule PET Probes for Neuroinflammation Imaging: Challenges and Opportunities beyond TSPO

“…PDE4D has been demonstrated to be involved in neuroinflammation, and an inhibition of PDE4D could attenuate neuroinflammation and provide neuroprotection in AD. 104 Recently, four lead PDE4D inhibitors were labeled with carbon-11 and evaluated in mice and monkeys with PET ( )), which exhibited an excellent binding affinity (IC 50 = 5.12, 0.5, 3.9, and 2.8 nM, respectively), high selectivity (>100-fold over PDE4B), and moderate brain uptake in mouse and, in particular, in monkey brains (mice: SUV max = 0.94, 1.44, 1.76, and 1.76, respectively, monkeys: SUV max = 4.32, 5.09, 3.28, and 3.52, respectively) (Figure 12). 105 PDE7 is another subtype of PDEs, which is involved in proinflammatory processes.…”