Neurodegenerative Disease Alzheimer’s Disease Figure 1: Hallmarks of Alzheimer’s Disease
followed by mitochondrial dysfunction and neuronal damage. Reactive species generated by mitochondria have several cellular targets, including mitochondrial components themselves (lipids, proteins and DNA). The lack of histones in mitochondrial DNA (mtDNA) and diminished capacity for DNA repair render mitochondria an especially vulnerable target of oxidative stress events.15
SP NFT
The central nervous system (CNS) is particularly susceptible to reactive species-induced damage16
because: it has a high consumption of
oxygen; it contains high levels of membrane polyunsaturated fatty acids susceptible to free radical attack; it is relatively deficient in oxidative defences (poor catalase activity and moderate SOD and GPx activities); and a high content in iron and ascorbate can be found in some regions of the CNS, enabling generation of more reactive species through the Fenton/Haber–Weiss reactions.
The neuropathological features associated with the disease include the presence of extracellular senile plaques (SPs) and intracellular neurofibrillary tangles (NFTs) and the loss of basal forebrain cholinergic neurons that innervate the hippocampus and the cortex. NFTs are formed from paired helical filaments composed of neurofilaments and hyperphosphorylated tau protein. SPs are formed mostly from the deposition of amyloid β (Aβ) peptide, a 39–43 amino acid peptide generated through the proteolytic cleavage of a larger amyloid β precursor protein (APP).
Figure 2: Mitochondrial Dysfunction in Alzheimer’s Disease
Endonuclease G DNA fragmentation AIF Cytochrome C APAF-1
Mitochondrial Cascade Theory of Alzheimer’s Disease
Loss of Ca2+ uptake
Caspase 9 Cytochrome C dATP H+ H+ H+ H+
Intermembrane space
Inner H2O O2 O2-• O2 ADP+Pi ATP
membrane Matrix
Apoptosis
Mitochondrial abnormalities associated with enhanced oxidative stress have long been recognised to play a major role in the cell degeneration and death that occur in Alzheimer’s disease (AD). Indeed, during AD evolution mitochondria suffer profound alterations that lead to reduced generation of adenosine triphosphate (ATP) and enhanced production of reactive oxygen species. Mitochondria also lose their Ca2+ buffering capacity, which can initiate a deleterious cascade within the cell. Impaired mitochondria also release several pro-apoptotic factors upon induction of apoptosis. These factors may directly trigger apoptosis by associating with cytosolic factors to form the apoptosome. Finally, some mitochondrial, pro-apoptotic proteins translocate into the nucleus to induce DNA fragmentation. Altogether these mitochondrial alterations contribute to cell degeneration and death. AIF = apoptosis-inducing factor; APAF-1 = protease-activating factor 1; Ca2+= calcium; dATP = 2´-deoxyadenosine 5´-triphosphate; O2
-•= superoxide. harmful or beneficial to living systems.14 Beneficial effects of reactive
species occur at low to moderate concentrations and involve physiological roles in cellular responses to noxia, as for example in defence against infectious agents and in the functioning of a number of cellular signalling systems. One further beneficial example of ROS at low to moderate concentrations is the induction of a mitogenic response.14
Caspase 3 activation
The amyloid cascade hypothesis has been evoked to explain the pathology that underlies AD. This hypothesis claims that deposition of Aβ is the causative agent of AD pathology and that NFT, cell loss, vascular damage and dementia follow as a direct result of this deposition.19
Mitochondria also serve as high-capacity Ca2+ sinks, which allows them to stay in tune with changes in cytosolic Ca2+ loads and aids in maintaining cellular Ca2+ homeostasis, which is required for normal neuronal function.17
Conversely, excessive Ca2+ uptake into
mitochondria has been shown to increase ROS production, inhibit ATP synthesis, induce mitochondrial permeability transition pore (PTP) and release small proteins that trigger the initiation of apoptosis, such as cytochrome C and apoptosis-inducing factor (AIF), from the mitochondrial intermembrane space into the cytoplasm. Released cytochrome C binds apoptotic protease activating factor 1 (Apaf-1) and activates the caspase cascade.18
Such alterations in
mitochondrial function have been proposed as a causative mechanism in the pathogenesis of AD (see Figure 2).
Accumulating evidence suggests that although the amyloid cascade hypothesis is potentially viable in familial AD cases, it may not apply in its current form to the sporadic type of the disease.20 First, persons with sporadic AD generally lack mutations in APP, PS1 and PS2 genes, so it is unclear what initiates plaque formation in such cases. Second, plaques are a relatively common finding in the non- demented elderly.21,22
Third, pathways through which plaques generate
NFTs and other recently described AD pathophysiological processes are unknown. These include neuronal apoptosis, neuronal aneuploidy and cerebral/extracerebral mitochondrial dysfunction.20,23–25
So,
important questions remain concerning late-onset sporadic AD: what triggers deposition of Aβ?; and what lies upstream?
Swerdlow and Khan26 proposed the mitochondrial cascade hypothesis,
However, oxidative stress occurs if the amount of free radical species produced overwhelms the cell’s capacity (enzymatic and non-enzymatic antioxidant defences) to neutralise them, which is
18
which attempts to connect all the pathological features of the disease. In this model, the individual’s genetics determine the basal rates of ROS production by the ETC, which determine the pace at which acquired mitochondrial damage accumulates. In turn, oxidative alterations induced in mitochondrial nucleic acids, lipids and proteins amplify ROS production and trigger three events: a reset response, in which cells respond to elevated ROS by generating Aβ, which further perturbs mitochondrial function; a removal response, in which compromised cells are purged via programmed cell death mechanisms; and a replace response, in which neuronal progenitors
EUROPEAN NEUROLOGICAL REVIEW
Degenerating neuron
Degenerating neuron
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