Background

Alzheimer’s disease (AD) is the most common cause of dementia and accelerates with advancing age. The most prominent symptoms of the disease are the progressive decline in cognitive functions and memory. AD is characterized by three major neuropathological hallmarks: senile plaques composed of amyloid β (Aβ) peptides, intracellular neurofibrillary tangles, and neuronal loss. The loss of neurons and synapses spreads to the hippocampus, entorhinal cortex, and frontal cortex, all of which play important roles in reference and working memory [1, 2]. In particular, the hippocampus is critical for learning and memory as well as mood regulation, and adult neurogenesis is necessary for its normal function [3, 4]. Adult hippocampal neurogenesis is known to contribute to the processing and the storage of new information [5, 6]. In AD brains the pathophysiological environment could have adverse effects on neurogenesis [7]. While memory deficits observed in AD could be linked to alterations in hippocampal neurogenesis [8, 9] we still need to actively investigate how neurogenesis is linked to cognitive function and whether stimulating regenerative mechanisms in the brain could restore or prevent further deterioration of cognition during the disease process. During the process of synaptic strengthening and memory formation a variety of molecular mechanisms are activated. The cyclic adenosine monophosphate (cAMP)/cAMP-response element binding protein (CREB) pathway may regulate the transcription of genes controlling these processes. Many neurodegenerative diseases are associated with aberrant cyclic nucleotide signalling related to phosphodiesterase (PDE) expression. PDEs are key enzymes in the cAMP signalling cascade. In AD brains, changes in cAMP-specific PDE mRNA expression were detected [10, 11]. PDE7 inhibition has been implicated in inflammation and neurodegenerative disorders [12, 13]. Peripheral administration of S14, a small heterocyclic molecule able to inhibit the cAMP-specific PDE7, produced anxiolytic-like effects, restored visual short-term memory, and decreased different pathological hallmarks in brains of APP/PS1 mice [14]. S14 treatment also induced in vitro and in vivo proliferation of neural stem cells, promoting their differentiation toward a dopaminergic phenotype in the substantia nigra of hemiparkinsonian rats [15]. More recently, the PDE7 inhibitor showed a significant increase in newly generated neurons in the olfactory bulb and the hippocampus of adult rats [16]. While PDE inhibitors have demonstrated neurotrophic, neuroprotective, and immunomodulatory potencies in AD models, little is known about the role of PDE7 in hippocampal neurogenesis in AD and its effects on learning and memory.

Through activation of peroxisome proliferator-activated receptor γ co-activator α (PGC-1α) and regulating p62 degradation, the cAMP/CREB pathway may also control mitochondrial dynamics and autophagy, respectively [63]. Since mitochondrial dysfunction is involved in many neurodegenerative diseases and aging [64], S14 may slow down pathological events in the neurodegenerative process.

Conclusions

In conclusion, our data provide evidence that PDE7 inhibition improved hippocampal neurogenesis and memory by modulating cAMP/pCREB activity and that these effects may be associated with mitochondrial dynamics regulation. Considering that S14 treatment has been reported to be beneficial for AD [14] and other neurodegenerative disorders such as Parkinson’s disease [15, 30, 37], this study suggests that S14 is a very promising disease-modifying drug candidate for the future treatment of neurodegenerative disorders.