Oxygen, a promoter of life or a mediator of death?

We are all familiar with processes like the rusting of iron, oil and butter turning rancid and fruits turning brown after prolonged exposure to air. All these phenomena are caused by exposure to oxygen in a process known as oxidation. Similar effects are known to happen inside our bodies in the molecular and cellular level, all because of the destructive action of a form of oxygen known as Reactive Oxygen Species (ROS). This destructive nature of oxygen comes in contrast to its unconditional necessity for the survival of all living aerobic organisms.

ROS are generated as by-products of cellular metabolism primarily at the mitochondria. They are unstable and highly reactive species that need to interact with other cellular components in order to be stabilized. Since their targets are DNA, lipids and proteins, this process (oxidation) can lead to DNA damage (mutations, deletions), membrane damage, reduced energy production by the mitochondria and eventually may induce cell death through apoptosis. On the other hand, the immune system uses the destructive power of ROS as a “blunt” weapon to combat invading pathogens.

The term oxidative stress is used to describe a state in which the equilibrium between the production of ROS and the body’s protective mechanisms (antioxidants and repair mechanisms) has been compromised, resulting in the oxidative damage of cells, tissues and organs. Moreover, ROS in the state of oxidative stress can impair several cellular signaling pathways that may result in the onset of age related diseases.

Oxidative stress and “normal aging”

Aging is a normal process of the human body that involves the progressive aberration of physiological functions in various tissues. This process is inevitable and may lead to different age related diseases and eventually death.

Aging is closely linked with the effects of oxidative stress and especially mitochondrial oxidative stress (1). As mentioned above, oxidative stress can damage the major constituents of the cell, specifically proteins, lipids and nucleic acids (DNA). This is the basis of the most popular hypothesis of aging that was first developed by Harman in 1957 and states that the accumulations of damaged molecules, including oxidatively induced DNA mutations, is responsible for the gradual deterioration of several physiological functions and the onset of various diseases (2). The role of mitochondria, the cell’s energy factories, in this process is believed to be critical since they are the major contributors of ROS (3) and could be considered a hallmark of cellular aging. Increased ROS production in the mitochondria may affect human life span through two different pathways: (i) by affecting sensitive signal transduction pathways leading to the onset of age-related degenerative diseases and (ii) by damaging mitochondrial DNA (mutations), proteins and lipids (membrane damage) limiting the life span of the cells (4).

In conclusion, aging is a normal process closely linked to oxidative stress and mediated mostly by mitochondria. Apart from the damage to lipids, proteins and DNA and their obvious consequences, oxidative stress can also impair signal transduction pathways and may be involved, combined with other factors such as inflammatory processes, in the onset of age-related diseases including cancer (5) and Alzheimer’s disease.

1. Chakravarti B and Chakravarti DN (2007), Gerontology, 53(3): 128-139.
2. Cutler RG and Mattson MP (2006), Ageing Research Reviews, 5:221-238
3. Lee HC and Wei YH (2007), Exp Biol Med (Maywood), 232(5): 592-606.
4. Sastre J et al (2003), Free Rad Biol Med, 35(1): 1-8
5. Fruehauf J.P. and Meyskens F.L. (2007), Clin Cancer Res, 13(3): 789-794.

Oxidative stress and Alzheimer’s Disease

Maintaining a well regulated balance between oxidizing species and antioxidant protective mechanisms in the brain is important for proper neuronal function. Neurons are especially prone to oxidative stress due to their high oxygen need and consumption, the low levels of classic antioxidants, the high content in unsaturated lipids of the neuronal membranes and the limited regeneration of damaged neurons (mitotic renewal) (1). Normally, the antioxidant defense mechanisms are sufficient to prevent oxidative stress by blocking ROS mediated damage. However, neurodegenerative age-related diseases like Alzheimer’s are associated with increased oxidative stress which precedes the development of the disease hallmark pathologies (2). Moreover, several recent scientific publications claim that oxidative stress, rather than amyloid beta and tau depositions, plays an important role in the Alzheimer’s disease pathogenesis (3, 4, 5). Interestingly, there is evidence that amyloid beta acts initially as an antioxidant protecting the neurons against oxidative stress and later, as the disease progresses and amyloid beta protein aggregates in senile plaques it becomes toxic and acts as a pro-oxidant (6, 7).

More importantly, these reports imply that therapeutic approaches that target the amyloid beta protein may be proven to be short-sighted and may even cause more harm than good if used early in the development of the disease.

1. Zhu X et al (2005), Mol Neurobiol, 31:205-217
2. Smith MA et al (2005), Neurobiol of Aging, 26:579-580
3. Nunomura A et al (2006), J Neuropathol Exp Neurol, 65(7): 631-641
4. Smith MA et al (2000), Biochimica et Biophysica Acta, 1502:139-144
5. Castellani RJ et al (2006), Am J Alzheimers Dis Other Demen, 21(2): 126-130
6. Kontush A et al (2001), Free Rad Biol Med, 30(1): 119-128
7. Kontush A (2001), Free Rad Biol Med, 31(9): 1120-1131

Alzheimer’s Disease: amyloid-beta accumulation or oxidative stress

As the earth’s population is becoming older, Alzheimer’s disease incidence is continually growing and expected to reach epidemic proportions by 2050. It is estimated that currently there are 26.6 million people living with the disease while this number is expected to surpass 106 million people, worldwide, by 2050 (1). The cost of the disease for patients, caregivers and healthcare is enormous, especially in the severe Alzheimer’s cases which require full time care from specialized personnel and facilities. Yet, we are still short from the launch of a disease modifying treatment while currently available drugs are only treating the symptoms. Nevertheless, these symptom treating drugs earned revenues of $2.41 billion in 2006 according to Frost & Sullivan (2). There is a tremendous medical unmet need here, that if satisfied by a disease modifying drug, the earnings could reach blockbuster levels.

Which is the best approach for treatment? The best approach should be the one that is targeted to the root of the problem, the cause of the disease. Such a therapy should be able to stop or, even better, reverse the progression of the disease. The cause of the disease, however, is still elusive. Currently, there are two major hypotheses concerning the cause of Alzheimer’s; the amyloid-beta cascade hypothesis and the alternative, oxidative stress hypothesis. The first hypothesis states that production and accumulation of the toxic amyloid-beta peptide in the formation of amyloid plaques is causing oxidative stress and subsequent neurodegeneration while the second states that oxidative stress is the cause of neurodegeneration and precedes the formation of amyloid plaques (3). Although both cases have strong evidence in their favor, approaches for the development of novel drugs based on the first hypothesis have failed so far to produce significant results. For example a recent study has shown that even though currently available cholinesterase inhibitors may reduce the amount of amyloid-beta, they are still unable to offer substantial benefit in terms of treatment (4). Moreover, the second hypothesis seems to be able to explain certain points that cannot be explained by the first including the following:

Dissociation of the link between amyloid-beta load and neuronal function since there are reports of cognitively intact aged individuals with amyloid-beta loads equivalent to those seen on Alzheimer’s patients (5).

Amyloid-beta peptides are not necessary harmful especially at the beginning of the disease before their massive accumulation and the formation of plaques. It has been reported that amyloid-beta peptide production may be a protective mechanism due to its anti-oxidant properties. Likewise, tau phosphorylation, another invariant feature of AD, is also a consequence of oxidative stress (6, 7, 8, 9).

There is weak correlation between amyloid-beta load and severity of the disease (neuronal loss or cognitive problems) (10, 11).

There is no doubt that amyloid-beta senile plaques and neurofibrillary tangles (tau protein) are both hallmark pathologies associated with the disease. Their role, however, as causative factors of the disease are not clear. They simply are pathologoanatomic findings and may not be causative factors of Alzheimer’s disease. In addition, formation of Aβ senile plaques is not exclusive to AD patients but is rather a normal process that occurs during aging (12).

Based on the above, it seems that the desired characteristics of a novel drug with blockbuster potential should be anti-amnesic effects to initially treat the symptoms, combined with neuroprotective effects to protect the degeneration of neurons rather than anti amyloid-beta properties. The scientific community is increasingly supporting this approach through numerous related publications.

1. Forecasting the global burden of Alzheimer’s disease” published in Alzheimer’s & Dementia, July 2007, vol 3, no 3.
2. U.S. Alzheimer’s Disease Medication Markets (2007) Frost & Sullivan analysis report.
3. Lee et al. (2007), J Pharmacol Exp Ther, 321(3): 823-829.
4. Ballard CG et al. (2007), Neurobiology, 68: 1726-1729.
5. Davis et al. (1999), J Neuropathol Exp Neurol, 58: 376-388.
6. Kontush A et al. (2001), Free Rad Biol Med, 30(1): 119-128.
7. Kontush A (2001), Free Rad Biol Med, 31(9): 1120-1131.
8. Castellani et al. (2006), Am J Alzheimers Dis Other Demen, 21(2): 126-130.
9. Smith MA et al (2005), Neurobiol of Aging, 26:579-580
10. Giannakopoulos et al. (2003), Neurology, 60:1495-1500.
11. Guillozet et al. (2003), Arch Neurol, 60:729-736.
12. Davies et al. (1998), Neurology, 38:1688-1693.

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