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)