Amyloid β-induced impairments on mitochondrial dynamics, hippocampal neurogenesis, and memory are restored by phosphodiesterase 7 inhibition

Alzheimer's Research & Therapy, Feb 2018

Fernando Bartolome, Macarena de la Cueva, Consuelo Pascual, Desiree Antequera, Tamara Fernandez, Carmen Gil, Ana Martinez, Eva Carro

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Amyloid β-induced impairments on mitochondrial dynamics, hippocampal neurogenesis, and memory are restored by phosphodiesterase 7 inhibition

Bartolome et al. Alzheimer's Research & Therapy Amyloid β-induced impairments on mitochondrial dynamics, hippocampal neurogenesis, and memory are restored by phosphodiesterase 7 inhibition Fernando Bartolome 0 1 3 Macarena de la Cueva 0 1 Consuelo Pascual 1 Desiree Antequera 1 3 Tamara Fernandez 1 Carmen Gil 2 Ana Martinez 2 Eva Carro 1 3 0 Equal contributors 1 Group of Neurodegenerative Diseases, Hospital 12 de Octubre Research Institute (imas12) , 28041 Madrid , Spain 2 Centro de Investigaciones Biológicas-CSIC , Ramiro de Maeztu 9, 28040 Madrid , Spain 3 Networked Biomedical Research Center in Neurodegenerative Diseases (CIBERNED) , 28031 Madrid , Spain 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. Phosphodiesterase; Alzheimer's disease; Transgenic mice; Oral administration; Memory; Hippocampus; Neurogenesis; Mitochondria; Mitophagy 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 hippoca (...truncated)


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Fernando Bartolome, Macarena de la Cueva, Consuelo Pascual, Desiree Antequera, Tamara Fernandez, Carmen Gil, Ana Martinez, Eva Carro. Amyloid β-induced impairments on mitochondrial dynamics, hippocampal neurogenesis, and memory are restored by phosphodiesterase 7 inhibition, Alzheimer's Research & Therapy, 2018, pp. 24, Volume 10, Issue 1, DOI: 10.1186/s13195-018-0352-4