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Mitochondrial Dysfunction Contributes to the Pathogenesis of Alzheimer's Disease.

Cabezas-Opazo FA, Vergara-Pulgar K, Pérez MJ, Jara C, Osorio-Fuentealba C, Quintanilla RA - Oxid Med Cell Longev (2015)

Bottom Line: Currently, there is no effective treatment for AD, which indicates the necessity to understand the pathogenic mechanism of this disorder.Mitochondria are essential for brain cells function and the improvement of mitochondrial activity contributes to preventing neurodegeneration.These defects affect mitochondrial health, which later will contribute to the pathogenesis of AD.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Neurodegenerative Diseases, Centro de Investigación Biomédica, Universidad Autónoma de Chile, San Miguel, 8900000 Santiago, Chile.

ABSTRACT
Alzheimer's disease (AD) is a neurodegenerative disease that affects millions of people worldwide. Currently, there is no effective treatment for AD, which indicates the necessity to understand the pathogenic mechanism of this disorder. Extracellular aggregates of amyloid precursor protein (APP), called Aβ peptide and neurofibrillary tangles (NFTs), formed by tau protein in the hyperphosphorylated form are considered the hallmarks of AD. Accumulative evidence suggests that tau pathology and Aβ affect neuronal cells compromising energy supply, antioxidant response, and synaptic activity. In this context, it has been showed that mitochondrial function could be affected by the presence of tau pathology and Aβ in AD. Mitochondria are essential for brain cells function and the improvement of mitochondrial activity contributes to preventing neurodegeneration. Several reports have suggested that mitochondria could be affected in terms of morphology, bioenergetics, and transport in AD. These defects affect mitochondrial health, which later will contribute to the pathogenesis of AD. In this review, we will discuss evidence that supports the importance of mitochondrial injury in the pathogenesis of AD and how studying these mechanisms could lead us to suggest new targets for diagnostic and therapeutic intervention against neurodegeneration.

No MeSH data available.


Related in: MedlinePlus

Improving mitochondrial health in AD. In AD, the action of tau and Aβ generates impairment of the mitochondrial function causing fragmentation, depolarization, oxidative stress, and defects in axonal transport. Several strategies have been used to reduce mitochondrial failure in AD. These elements include antioxidants (systemic and mitochondria-targeted), inhibitors of mitochondrial dynamics, microtubules stabilizing drugs, and increase of mitochondrial biogenesis. Also, in this review, we propose the use of a “double mitochondrial therapy,” which means the combinatory use of mitotargeted antioxidants and activators of mitochondrial biogenesis. The use of these therapies can potentially reduce the mitochondrial fragmentation improving the mitochondrial network, restore the membrane potential (increasing ATP production and reducing ROS levels), and increase axonal transport. ΔΨ: mitochondrial membrane potential; VDAC1: voltage-dependent anion channel; HDAC6: histone deacetylase 6; Nrf2: nuclear factor erythroid 2-related factor 2; PGC1-α: peroxisome proliferator-activated receptor gamma-coactivator 1 alpha.
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fig2: Improving mitochondrial health in AD. In AD, the action of tau and Aβ generates impairment of the mitochondrial function causing fragmentation, depolarization, oxidative stress, and defects in axonal transport. Several strategies have been used to reduce mitochondrial failure in AD. These elements include antioxidants (systemic and mitochondria-targeted), inhibitors of mitochondrial dynamics, microtubules stabilizing drugs, and increase of mitochondrial biogenesis. Also, in this review, we propose the use of a “double mitochondrial therapy,” which means the combinatory use of mitotargeted antioxidants and activators of mitochondrial biogenesis. The use of these therapies can potentially reduce the mitochondrial fragmentation improving the mitochondrial network, restore the membrane potential (increasing ATP production and reducing ROS levels), and increase axonal transport. ΔΨ: mitochondrial membrane potential; VDAC1: voltage-dependent anion channel; HDAC6: histone deacetylase 6; Nrf2: nuclear factor erythroid 2-related factor 2; PGC1-α: peroxisome proliferator-activated receptor gamma-coactivator 1 alpha.

Mentions: Despite the potential benefits of choosing one pathway or another to improving mitochondrial injury in AD, the use of a different strategy that simultaneously activates mitochondrial function by two pathways could have more positive effects. For instance, the use of scavenger's compounds or specific antioxidants for mitochondria showed an important reduction in ROS levels and partially recovered mitochondrial function in neurons [99]. However, if we consider that some elements that control mitochondrial biogenesis contributed to mitochondrial impairment in AD, the use of antioxidants will not correct this deficiency. At the same time, preventing mitochondrial dysfunction through activation of PGC1-α and/or Nrf2 pathways requires a complex regulation with no immediate results [102, 105]. In this scenario, the use of mitochondrial antioxidants in combination with activators of mitochondrial biogenesis could have more promising results (Figure 2) [110, 111]. These observations rest on studies discussed in this review, which indicates that mitochondrial dysfunction could be responsible for the neurodegeneration in AD by affecting energy supply and reducing antioxidant defenses. Moreover, mitochondrial injury could participate in the establishment of Aβ and tau pathology, two hallmarks in the pathogenesis of AD [93] (Figure 2). However, further studies are needed to explore this strategy as a valid target to prevent mitochondrial injury in AD.


Mitochondrial Dysfunction Contributes to the Pathogenesis of Alzheimer's Disease.

Cabezas-Opazo FA, Vergara-Pulgar K, Pérez MJ, Jara C, Osorio-Fuentealba C, Quintanilla RA - Oxid Med Cell Longev (2015)

Improving mitochondrial health in AD. In AD, the action of tau and Aβ generates impairment of the mitochondrial function causing fragmentation, depolarization, oxidative stress, and defects in axonal transport. Several strategies have been used to reduce mitochondrial failure in AD. These elements include antioxidants (systemic and mitochondria-targeted), inhibitors of mitochondrial dynamics, microtubules stabilizing drugs, and increase of mitochondrial biogenesis. Also, in this review, we propose the use of a “double mitochondrial therapy,” which means the combinatory use of mitotargeted antioxidants and activators of mitochondrial biogenesis. The use of these therapies can potentially reduce the mitochondrial fragmentation improving the mitochondrial network, restore the membrane potential (increasing ATP production and reducing ROS levels), and increase axonal transport. ΔΨ: mitochondrial membrane potential; VDAC1: voltage-dependent anion channel; HDAC6: histone deacetylase 6; Nrf2: nuclear factor erythroid 2-related factor 2; PGC1-α: peroxisome proliferator-activated receptor gamma-coactivator 1 alpha.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4499633&req=5

fig2: Improving mitochondrial health in AD. In AD, the action of tau and Aβ generates impairment of the mitochondrial function causing fragmentation, depolarization, oxidative stress, and defects in axonal transport. Several strategies have been used to reduce mitochondrial failure in AD. These elements include antioxidants (systemic and mitochondria-targeted), inhibitors of mitochondrial dynamics, microtubules stabilizing drugs, and increase of mitochondrial biogenesis. Also, in this review, we propose the use of a “double mitochondrial therapy,” which means the combinatory use of mitotargeted antioxidants and activators of mitochondrial biogenesis. The use of these therapies can potentially reduce the mitochondrial fragmentation improving the mitochondrial network, restore the membrane potential (increasing ATP production and reducing ROS levels), and increase axonal transport. ΔΨ: mitochondrial membrane potential; VDAC1: voltage-dependent anion channel; HDAC6: histone deacetylase 6; Nrf2: nuclear factor erythroid 2-related factor 2; PGC1-α: peroxisome proliferator-activated receptor gamma-coactivator 1 alpha.
Mentions: Despite the potential benefits of choosing one pathway or another to improving mitochondrial injury in AD, the use of a different strategy that simultaneously activates mitochondrial function by two pathways could have more positive effects. For instance, the use of scavenger's compounds or specific antioxidants for mitochondria showed an important reduction in ROS levels and partially recovered mitochondrial function in neurons [99]. However, if we consider that some elements that control mitochondrial biogenesis contributed to mitochondrial impairment in AD, the use of antioxidants will not correct this deficiency. At the same time, preventing mitochondrial dysfunction through activation of PGC1-α and/or Nrf2 pathways requires a complex regulation with no immediate results [102, 105]. In this scenario, the use of mitochondrial antioxidants in combination with activators of mitochondrial biogenesis could have more promising results (Figure 2) [110, 111]. These observations rest on studies discussed in this review, which indicates that mitochondrial dysfunction could be responsible for the neurodegeneration in AD by affecting energy supply and reducing antioxidant defenses. Moreover, mitochondrial injury could participate in the establishment of Aβ and tau pathology, two hallmarks in the pathogenesis of AD [93] (Figure 2). However, further studies are needed to explore this strategy as a valid target to prevent mitochondrial injury in AD.

Bottom Line: Currently, there is no effective treatment for AD, which indicates the necessity to understand the pathogenic mechanism of this disorder.Mitochondria are essential for brain cells function and the improvement of mitochondrial activity contributes to preventing neurodegeneration.These defects affect mitochondrial health, which later will contribute to the pathogenesis of AD.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Neurodegenerative Diseases, Centro de Investigación Biomédica, Universidad Autónoma de Chile, San Miguel, 8900000 Santiago, Chile.

ABSTRACT
Alzheimer's disease (AD) is a neurodegenerative disease that affects millions of people worldwide. Currently, there is no effective treatment for AD, which indicates the necessity to understand the pathogenic mechanism of this disorder. Extracellular aggregates of amyloid precursor protein (APP), called Aβ peptide and neurofibrillary tangles (NFTs), formed by tau protein in the hyperphosphorylated form are considered the hallmarks of AD. Accumulative evidence suggests that tau pathology and Aβ affect neuronal cells compromising energy supply, antioxidant response, and synaptic activity. In this context, it has been showed that mitochondrial function could be affected by the presence of tau pathology and Aβ in AD. Mitochondria are essential for brain cells function and the improvement of mitochondrial activity contributes to preventing neurodegeneration. Several reports have suggested that mitochondria could be affected in terms of morphology, bioenergetics, and transport in AD. These defects affect mitochondrial health, which later will contribute to the pathogenesis of AD. In this review, we will discuss evidence that supports the importance of mitochondrial injury in the pathogenesis of AD and how studying these mechanisms could lead us to suggest new targets for diagnostic and therapeutic intervention against neurodegeneration.

No MeSH data available.


Related in: MedlinePlus