Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder mainly known for synaptic impairment and neuronal cell loss, affecting memory processes. Beside these damages, mitochondria have been implicated in the pathogenesis of AD through the induction of the mitochondrial permeability transition pore (mPTP). The mPTP is a non-selective pore that is formed under apoptotic conditions, disturbing mitochondrial structure and thus, neuronal viability. In AD, Aβ oligomers (Aβos) favor the opening of the pore, activating mitochondria-dependent neuronal cell death cascades. The Wnt signaling activated through the ligand Wnt3a has been described as a neuroprotective signaling pathway against amyloid-β (Aβ) peptide toxicity in AD. However, the mechanisms by which Wnt signaling prevents Aβos-induced neuronal cell death are unclear. We proposed here to study whether Wnt signaling protects neurons earlier than the late damages in the progression of the disease, through the preservation of the mitochondrial structure by the mPTP inhibition. To study specific events related to mitochondrial permeabilization we performed live-cell imaging from primary rat hippocampal neurons, and electron microscopy to analyze the mitochondrial morphology and structure. We report here that Wnt3a prevents an Aβos-induced cascade of mitochondrial events that leads to neuronal cell death. This cascade involves (a) mPTP opening, (b) mitochondrial swelling, (c) mitochondrial membrane potential loss and (d) cytochrome c release, thus leading to neuronal cell death. Furthermore, our results suggest that the activation of the Wnt signaling prevents mPTP opening by two possible mechanisms, which involve the inhibition of mitochondrial GSK-3β and/or the modulation of mitochondrial hexokinase II levels and activity. This study suggests a possible new approach for the treatment of AD from a mitochondrial perspective, and will also open new lines of study in the field of Wnt signaling in neuroprotection.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss and cognitive decline [1]
Our results suggest that the mitochondrial permeability transition pore (mPTP) inhibition observed in response to Wnt signaling activation is mediated by the inhibition of glycogen synthase kinase-3β (GSK-3β) via 2 possible mechanisms, namely via modulation of the mitochondrial detachment/translocation process of hexokinase II (HKII) and via the interaction of phosphorylated GSK-3β with adenine nucleotide translocase (ANT) in the mPTP protein complex
The mPTP opening was stimulated with Aβos, and as a result of permeabilization of the mitochondrial inner membrane the mitochondrial calcein fluorescence rapidly decayed in control neurons, whereas Wnt3a-treated neurons did not show any obvious changes in response to Aβos (Fig 1A)
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss and cognitive decline [1]. In AD, Aβos facilitate the interaction of CypD with the other components to form an open and irreversible conformation of the pore [13]. Mitochondrial swelling occurs along with several mitochondrial perturbations, including multiple cellular stresses as ROS generation, calcium deregulation, mitochondrial membrane potential collapse, and the release of pro-apoptotic factors into the cytoplasm, such as cytochrome c. These mitochondrial perturbations, known as the “mitochondrial cascade hypothesis in AD”, precede the synaptic damage, the neuronal cell death, and the deficits in learning/memory ability in AD [6,14]
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