Phosphodiesterase-4D Knockdown in the Prefrontal Cortex Alleviates Memory Deficits and Synaptic Failure in Mouse Model of Alzheimer’s Disease

Abstract

Phosphodiesterase 4 (PDE4)-dependent cAMP signaling plays a crucial role in cognitive impairment associated with Alzheimer’s disease (AD). However, whether inhibition of PDE4 subtypes or their splice variants in the prefrontal cortex positively regulates synaptic plasticity and antioxidative stress, and reverses β-amyloid 1–42 (Aβ1–42, Aβ42)-induced cognitive impairment still need to be clarified. The present study determined whether and how PDE4D knockdown by microinjection of lenti-PDE4D-miRNA into the prefrontal cortex reversed Aβ1–42-induced cognitive impairment in behavioral, neurochemical, and molecular biology assays. The results suggested that PDE4D knockdown increased time to explore the novel object and decreased latency to leave the platform in novel object recognition and step-down passive avoidance tests. Further study suggested that PDE4D knockdown decreased the number of working memory errors in the eight-arm maze test. These effects were prevented by PKA inhibitor H89. The subsequent experiment suggested that inhibition of PDE4D in the prefrontal cortex rescued the long-term potentiation (LTP) and synaptic proteins’ expression; it also increased antioxidant response by increasing superoxide dismutase (SOD) and decreasing malondialdehyde (MDA) levels. PDE4D knockdown also increased phosphorylated cAMP response element-binding protein (pCREB), brain-derived neurotrophic factor (BNDF), and anti-apoptotic proteins’ expression, i.e., the ratio of Bcl-2/Bax, and decreased caspase-3 level in the prefrontal cortex. These findings extend the previous findings and support the hypothesis that RNA interference-mediated PDE4D knockdown in the prefrontal cortex ameliorated memory loss associated with synaptic failure in an AD mouse model by its antioxidant, anti-apoptotic, and neuroprotective properties.

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).…”

Mouse hybrid genome mediates diverse brain phenotypes with the specificity of reciprocal crosses

“…Indeed, several imprinted genes were related to behavioral functions. The second group, which involved the imprinted gene Ube3a , has been reported to regulate sleep homeostasis 57 ; the fifth group, which involved the imprinted gene Ntm , has been reported to be involved in motor function 58 ; the thirteenth group involved four imprinted genes ( Gpr1 , Nnat , Htra3 , and Pon2) , which regulate reproduction 59–62 ; and the fourteenth group involved four imprinted genes ( Dcd , 63 Ppo1r9a , 64 Slc22a2 , 65 and Pde4d 66 ) reported to mediate learning and memory.…”

Rolipram and pentoxifylline combination ameliorates the morphological abnormalities of dorsal root ganglion neurons in experimental diabetic neuropathy by reducing mitochondrial dysfunction and apoptosis

“…Rolipram also prevents the decline of MMP and reduction of ATP levels in neurodegenrative diseases. [48][49][50][51][52] Previous studies have also shown that pentoxifylline inhibits the phosphodiesterase enzyme and enhances cellular cAMP and ATP, which may contribute to alleviate DN. [25,53] This effect seems to be related to the antiapoptotic effect of pentoxifylline.…”