Abstract
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and is characterized by progressive memory loss and cognitive decline. One of the hallmarks of AD is the overproduction of amyloid-beta aggregates that range from the toxic soluble oligomer (Aβo) form to extracellular accumulations in the brain. Growing evidence indicates that mitochondrial dysfunction is a common feature of neurodegenerative diseases and is observed at an early stage in the pathogenesis of AD. Reports indicate that mitochondrial structure and function are affected by Aβo and can trigger neuronal cell death. Mitochondria are highly dynamic organelles, and the balance between their fusion and fission processes is essential for neuronal function. Interestingly, in AD, the process known as “mitochondrial dynamics” is also impaired by Aβo. On the other hand, the activation of the Wnt signaling pathway has an essential role in synaptic maintenance and neuronal functions, and its deregulation has also been implicated in AD. We have demonstrated that canonical Wnt signaling, through the Wnt3a ligand, prevents the permeabilization of mitochondrial membranes through the inhibition of the mitochondrial permeability transition pore (mPTP), induced by Aβo. In addition, we showed that non-canonical Wnt signaling, through the Wnt5a ligand, protects mitochondria from fission-fusion alterations in AD. These results suggest new approaches by which different Wnt signaling pathways protect neurons in AD, and support the idea that mitochondria have become potential therapeutic targets for the treatment of neurodegenerative disorders. Here we discuss the neuroprotective role of the canonical and non-canonical Wnt signaling pathways in AD and their differential modulation of mitochondrial processes, associated with mitochondrial dysfunction and neurodegeneration.
Highlights
Mitochondria are key organelles for proper neuronal function and viability, for their role in ATP production and for their tremendous capacity to buffer intracellular calcium (Ca2+; Celsi et al, 2009)
amyloid-β peptide (Aβ) can interact with several proteins that are important for the correct function of this organelle and/or for the maintenance of its structure, such as cyclophilin D (CypD), which participates in the opening of the mitochondrial permeability transition pore (mPTP) and regulates the permeability and function of mitochondria, affecting both their energetic and calcium buffering functions (Connern and Halestrap, 1994; Du and Yan, 2010b)
We showed by electron microscopy from hippocampal slices that, besides mPTP inhibition mediated by Wnt3a, this ligand can prevent the disruption of the mitochondrial membranes and mitochondrial swelling, since the volume and size of the organelle were conserved when Wnt signaling was activated, preserving the whole structure of the mitochondria even in the presence of Aβ oligomers (Aβo) (Arrázola and Inestrosa, 2013), and preventing the changes that occur in Alzheimer’s disease (AD) brains during mPTP opening (Moreira et al, 2001, 2002; Du and Yan, 2010b; Du et al, 2010)
Summary
Mitochondria are key organelles for proper neuronal function and viability, for their role in ATP production and for their tremendous capacity to buffer intracellular calcium (Ca2+; Celsi et al, 2009) Due to this important function in maintaining neuronal Ca2+ homeostasis, mitochondria have been indicated in the regulation of synaptic transmission (Billups and Forsythe, 2002). The increase in cytosolic Ca2+ directly affects mitochondria, disrupting their critical function as Ca2+ buffering organelles (Celsi et al, 2009), which disturbs ATP generation and neuronal viability For this reason, mitochondrial dysfunction appears an obligatory downstream step in the pathogenesis of AD
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