Wnt Signaling Prevents the Aβ Oligomer-Induced Mitochondrial Permeability Transition Pore Opening Preserving Mitochondrial Structure in Hippocampal Neurons

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.

Wnt‐induced activation of glucose metabolism mediates the in vivo neuroprotective roles of Wnt signaling in Alzheimer disease

“…At the end, the Wnt blockade will cause the downregulation of the oxidative phosphorylation leading to an altered cellular metabolism. In the context of AD, we showed that Wnt3a treatment prevents mitochondrial damage induced by Ab, possibly by inhibiting opening of the mitochondrial permeability transition pore (mPTP) (Arr azola et al 2017). Wnt signaling also stimulates glucose metabolism in neurons and this could promote the generation of ROS.…”

“…The ability of Ab to reduce cellular ATP production in vitro was blocked by Wnt3a treatment and this protective effect was abolished by an ATP synthase inhibitor. This suggests that the major deleterious effects of Ab are due, at least in part, to its effect on mitochondrial energy metabolism and that Wnt signaling exerts its neuroprotective role by restoring mitochondrial function in neurons (Arr azola et al 2017).…”

The Key Roles of GSK-3β in Regulating Mitochondrial Activity

“…However, APC and IPC do not facilitate the binding of phosphor-Ser9-GSK-3β to VDAC or CyP-D [52]. GSK-3β is a key factor in Wnt signaling, which has been reported to regulate the activity of mPTP [53]. Bcl-2 is the target gene of Wnt signaling to participate in the stabilization of mitochondria against Aβ damage.…”

Comprehensive Overview of Alzheimer’s Disease Neurodegeneration, from Amyloid-β to Neuroinflammatory Modulation

“…Moreover, it has been found that Aβ can also enter the mitochondria, leading directly to mitochondrial dysfunction and to altered energy metabolism within cells. Along with the reduction of available ATP, altered mitochondria will also increase the production of ROS contributing to increase the brain oxidative status and resulting in the production of additional pro-inflammatory mediators, such as IL-6 [44][45][46][47]. In this regard, once released to the extracellular compartment, ROS can further trigger the inflammatory pathways in the neighboring cells inducing the activation of the NF-kB-dependent pro-inflammatory cascade [20].…”