Mitochondrial Dysfunction and Oxidative Stress in Alzheimer’s Disease
unsuccessfully attempt to re-enter the cell cycle, with resultant aneuploidy, tau phosphorylation and NFT formation.26
In summary, this
hypothesis postulates that mitochondrial dysfunction represents a primary pathology in sporadic, late-onset AD, and drives both SP and NFT formation. It further provides a rationale for how mitochondrial dysfunction surpassing certain thresholds triggers compensatory mechanisms that cause the various pathological hallmarks of AD.26
Mitochondrial (Dys)function, Oxidative Stress and Cell Death Are Interlinked in Alzheimer’s Disease Several in vitro, in vivo and human studies indicate that AD is characterised by mitochondrial dysfunction, increased oxidative stress and neuron death (see Figure 2). Since this is a very extensive topic to discuss, some relevant data are presented following a simple scheme where findings are grouped according to the experimental system through which data were obtained.
In Vitro Studies Several in vitro studies have provided compelling evidence that Aβ might cause mitochondrial dysfunction. It was previously shown that Aβ requires functional mitochondria to induce toxicity.27 Hansson et al.28
Furthermore,
identified an active γ-secretase complex in rat brain mitochondria. Being composed of nicastrin (NCT), anterior pharynx- defective 1 (APH-1) and presenilin enhancer protein 2 (PEN2), this γ-secretase complex cleaves, among other substrates, APP, generating Aβ and APP-intracellular domain. Furthermore, the presence of APP was detected in mitochondrial membranes of PC12 cells bearing the Swedish double mutation in the APP gene.29 Together these studies placed mitochondria in a privileged position concerning APP processing and answered the ‘old question’ of how Aβ interacts with mitochondria.
Studies from our laboratory showed that Aβ peptides in the presence of Ca2+ exacerbate PTP opening.30,31
The PTP induction, a phenomenon
characterised by a sudden increase in the permeability of the inner mitochondrial membrane, plays a key role in apoptotic cell death by facilitating the release of apoptogenic factors. We observed that Aβ in the presence of Ca2+ decreases the mitochondrial transmembrane potential and the capacity of brain mitochondria to accumulate Ca2+, and induces a complete uncoupling of respiration and an alteration of the ultrastructural morphology of mitochondria characterised by swelling and disruption of mitochondria cristae.30,31
Altogether these
results suggest a clear association between Aβ, mitochondrial dysfunction and alteration of Ca2+ homeostasis. Du and collaborators32 showed that the interaction of cyclophilin D, an integral part of the PTP, with mitochondrial Aβ potentiates mitochondrial, neuronal and synaptic stress. It was also observed that cyclophilin D deficiency substantially improves learning and memory and synaptic function in an AD mouse model and alleviates Aβ-mediated reduction of long-term potentiation.32
We also observed that diabetes-related mitochondrial dysfunction is exacerbated by ageing and/or by the presence of Aβ, supporting the idea that diabetes and ageing are risk factors for the neuro- degeneration induced by this peptide.33–35
Ageing of diabetic rats
induces an impairment of the respiratory chain and a decrease in OXPHOS efficiency and in the capacity of mitochondria to accumulate
Ca2+. In the presence of Aβ25–35 or Aβ1–40, the age-related mitochondrial effects are potentiated.33
Additionally, brain mitochondria isolated from diabetic rats in the presence of Aβ1–40 produce higher levels of EUROPEAN NEUROLOGICAL REVIEW
However, insulin and co-enzyme Q10 (CoQ10) treatments prevent the decline in mitochondrial OXPHOS efficiency and avoid an increase in oxidative stress induced by Aβ.35
H2O2.34 It was also shown
that cultured neurons from transgenic (Tg) mice that overexpress a mutant form of APP and Aβ-binding alcohol dehydrogenase (ABAD)
(Tg mAPP/ABAD) display spontaneous generation of H2O2 and O2-•, decreased ATP levels, release of cytochrome C and induction of caspase 3-like activity followed by DNA fragmentation and loss of cell viability. Furthermore, generation of ROS is associated with a dysfunctional cyclo-oxygenase.36
Other studies from our laboratory also showed that pheochromocytoma
cells (PC12) exposed to Aβ1–40 and Aβ25–35 present mitochondrial dysfunction characterised by the inhibition of complexes I, III and IV of the mitochondrial respiratory chain.37 collaborators38
Recently, Rhein and
evaluated the mitochondrial respiratory functions and energy metabolism in control and in human wild-type APP stably transfected SH-SY5Y cells. The authors observed that complex IV activity is significantly reduced in APP cells. By contrast, a significant increase in the activity of complex III is observed. The authors interpreted this increase as a compensatory response in order to balance the defect of complex IV. However, this compensatory mechanism does not prevent the strong impairment of total respiration in APP cells. As a result, the respiration together with ATP production decreases in the APP cells in comparison with the control cells.38
We have previously shown that AD fibroblasts present high levels of oxidative stress and apoptotic markers compared with young and age-matched controls.39
Furthermore, AD-type changes could be
generated in control fibroblasts using N-methyl protoporphyrin to inhibit cytochrome oxidase (COX) assembly, indicating that the observed oxidative damage is associated with mitochondrial dysfunction. The effects of N-methyl protoporphyrin are reversed or attenuated by both lipoic acid and N-acetyl cysteine.39
These results
suggest that mitochondria are important in the oxidative damage that occurs in AD and that antioxidant therapies may represent promising therapeutic strategies. Recently, Wang and collaborators40
showed
that sporadic AD fibroblasts present alterations in mitochondria morphology and distribution.40
Mitochondrial abnormalities are
due to a decrease in dynamin-like protein 1 (DLP1), a regulator of mitochondrial fission and distribution. Further, Aβ overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins.41
In the same line, Cho and
collaborators found that NO• produced in response to Aβ triggers mitochondrial fission, synaptic loss and neuronal damage, in part via S-nitrosylation of DLP1.42
Interestingly, Abramov et al.43 reported that Aβ causes a loss of
mitochondrial potential in astrocytes but not in neurons. Since this effect is prevented by antioxidants and reversed by provision of glutamate and other mitochondrial substrates to complexes I and II, they suggested that the depolarisation reflects oxidative damage to metabolic pathways upstream of mitochondrial respiration. However, Paradisi et al.44
demonstrated that astrocytes can protect neurons
from Aβ neurotoxicity, but when they interact directly with Aβ, the protection is undermined and the neurotoxicity is enhanced.
Mitochondria in Ntera2 human teratocarcinoma (NT2 rh0+) cells
exposed to Aβ25–35 release cytochrome C, with subsequent activation of caspases 9 and 3.45
Marques et al.46 investigated the effect of the 19
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