Abstract
Background
The phosphodiesterase (PDE) 7 inhibitor S14 is a cell-permeable small heterocyclic molecule that is able to cross the blood–brain barrier. We previously found that intraperitoneal treatment with S14 exerted neuroprotection in an Alzheimer’s disease (AD) model (in APP/PS1 mice). The objective of this study was to investigate the neurogenic and cellular effects of oral administration of S14 on amyloid β (Aβ) overload.
Methods
We orally administered the PDE7 inhibitor S14 (15 mg/kg/day) or vehicle in 6-month-old APP/PS1 mice. After 5 weeks of S14 treatment, we evaluated cognitive functions and brain tissues. We also assessed the effects of S14 on the Aβ-treated human neuroblastome SH-SY5Y cell line.
Results
Targeting the cyclic adenosine monophosphate (cAMP)/cAMP-response element binding protein (CREB) pathway, S14 rescued cognitive decline by improving hippocampal neurogenesis in APP/PS1 transgenic mice. Additionally, S14 treatment reverted the Aβ-induced reduction in mitochondrial mass in APP/PS1 mice and in the human neuroblastoma SH-SY5Y cells co-exposed to Aβ. The restoration of the mitochondrial mass was found to be a dual effect of S14: a rescue of the mitochondrial biogenesis formerly slowed down by Aβ overload, and a reduction in the Aβ-increased mitochondrial clearance mechanism of mitophagy.
Conclusions
Here, we show new therapeutic effects of the PDE7 inhibitor, confirming S14 as a potential therapeutic drug for AD.
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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.
Abbreviations
- Aβ:
-
Amyloid β
- AD:
-
Alzheimer’s disease
- APP/PS1:
-
APPSWE/PS1M146L
- BrdU:
-
5-Bromo-2′-deoxyuridine
- cAMP:
-
Cyclic adenosine monophosphate
- CREB :
-
cAMP-response element binding protein
- CxVβ:
-
Complex V β subunit
- DAB:
-
3,3′-Diaminobenzidine
- DCX:
-
Doublecortin
- DMEM:
-
Dulbecco’s modified Eagle’s medium
- Drp1:
-
Dynamin-related protein 1
- FBS:
-
Fetal bovine serum
- HRP:
-
Horseradish peroxidase
- LC3:
-
Light chain 3
- Mfn1:
-
Mitofusin1
- Mfn2:
-
Mitofusin2
- NeuN:
-
Neuronal nuclei
- Opa1:
-
Optic atrophy 1
- PB:
-
Phosphate buffer
- PDE:
-
Phosphodiesterase
- PFA:
-
Paraformaldehyde
- PGC-1α:
-
Peroxisome proliferator-activated receptor γ co-activator α
- TMRM:
-
Tetramethyl-rhodamine methylester
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Acknowledgments
This study was supported by grants from the Instituto de Salud Carlos III (FIS2012/00486, FIS2015/00780), FEDER, Alzheimer’s Drug Discovery Foundation (grant no. 20121102), and CIBERNED. AM and CG are members of the “CIB Intramural Program “Molecular Machines for Better Life” (MACBET)”.
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EC, FB, and AM designed the research study. EC and FB wrote the manuscript. CP and DA performed the S14 administration and behavioural experiments. TF performed the immunohistochemical experiments. FB and MdlC performed the biochemical experiments. CG performed the S14 compound synthesis. AM and FB assisted in data analysis and discussion. All authors actively reviewed and edited the manuscript. All authors read and approved the final manuscript.
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Additional file
Additional file 1
Figure S1. Aβ-induced reduction in mitochondrial biogenesis in neurons is restored after S14 treatment. Mitochondrial mass was carried out in live rat neuronal primary cultures simultaneously exposed to 1 μM oligomeric Aβ42 for 24 h and evaluated by confocal imaging. Representative images showing the mitochondria and the whole cell body with the range of treatments are presented in the left panels. Imaging analysis revealed a reduced amount of mitochondrial volume from the whole cell volume in Aβ42-exposed cells compared to untreated cells. Treatment with 15 μM S14 on Aβ42-exposed cells obliterated this effect, showing no changes in the unexposed cells. Statistical significance was assessed by two-way ANOVA followed by Fisher’s post-hoc test for multiple comparisons. Data are expressed as mean ± SEM; n = 4; **p < 0.01; ****p < 0.0001. (JPEG 1623 kb)
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Bartolome, F., de la Cueva, M., Pascual, C. et al. Amyloid β-induced impairments on mitochondrial dynamics, hippocampal neurogenesis, and memory are restored by phosphodiesterase 7 inhibition. Alz Res Therapy 10, 24 (2018). https://doi.org/10.1186/s13195-018-0352-4
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DOI: https://doi.org/10.1186/s13195-018-0352-4