Amyloid-β peptides induce DNA fragmentation: an alternative pathway yet to be understood in Alzheimer disease pathology
The paper (Prestwich et al., 2005) has fascinated us and made us believe that we are in the right direction toward exploring an alternative pathway for the pathogenesis of the Alzheimer disease. Our earlier finding of amyloid-β peptides binding to and inducing conformational change in DNA (Hegde et al., 2004) led us to study the effect of amyloid-β peptides on DNA integrity. That other amyloidogenic peptides, such as α-synuclein and prion, also were found to bind to DNA (Veer Bala Gupta et al., 2006), made us argue that there is a common mechanism of action of these peptides at work in neurodegeneration. In this perspective, we highlighted an interesting mechanism of different molecular forms (monomer-oligomer aggregates) of amyloid-β and α-synuclein binding to DNA and inducing DNA damage (Hegde et al., 2004, Abstract). It also gives us insight into understanding the different events taking place at different stages of...  Read more

Amyloid-β peptides induce DNA fragmentation: an alternative pathway yet to be understood in Alzheimer disease pathology
The paper (Prestwich et al., 2005) has fascinated us and made us believe that we are in the right direction toward exploring an alternative pathway for the pathogenesis of the Alzheimer disease. Our earlier finding of amyloid-β peptides binding to and inducing conformational change in DNA (Hegde et al., 2004) led us to study the effect of amyloid-β peptides on DNA integrity. That other amyloidogenic peptides, such as α-synuclein and prion, also were found to bind to DNA (Veer Bala Gupta et al., 2006), made us argue that there is a common mechanism of action of these peptides at work in neurodegeneration. In this perspective, we highlighted an interesting mechanism of different molecular forms (monomer-oligomer aggregates) of amyloid-β and α-synuclein binding to DNA and inducing DNA damage (Hegde et al., 2004, Abstract). It also gives us insight into understanding the different events taking place at different stages of the disease in view of the changing conformation of these peptides in brain.

References:
1. Prestwich EG, Roy MD, Rego J, Kelley SO. Oxidative DNA strand scission induced by peptides. Chem Biol. 2005 Jun;12(6):695-701. Abstract

2. Hegde ML, Anitha S, Latha KS, Mustak MS, Stein R, Ravid R, Rao KS. First evidence for helical transitions in supercoiled DNA by amyloid Beta Peptide (1-42) and aluminum: a new insight in understanding Alzheimer's disease. J Mol Neurosci. 2004;22(1-2):19-31. Abstract

3. Veer Bala Gupta, Hegde ML, Jagannatha K.S The role of protein conformational dynamics and DNA integrity in neuronal Cell death in neurodegeneration. Curr. Alz. Res., 3 (4), (2006) in press.

4. M.L.Hegde, S.Anitha and Jagannatha K.S (2004) Are Monomer-Oligomer Aggregates of Amyloidogenic Peptides Toxic Species in Neurodegeneration, NeuroBiol Aging (Abstract) P1-261, 25, S2, 170.

View all comments by Veer Bala Gupta
View all comments by K.S. Jagannatha Rao

I partially agree with the suggestion that villagers in India who consume mustard oil didn't have AD in old age, also because it was found in current research that turmeric and mustard oil users are less susceptible to AD, but I disagree with his query that we can't relate AD with age as we have certain data for its proof. Age is the most important known risk factor for AD. The number of people with the disease doubles every 5 years beyond age 65. Middle-aged women are at greater risk than men (AD). A recent study shows that high blood pressure dramatically increases this risk, foretelling a potential epidemic of dementia as baby boomers enter their later years. Research at Boston University School of Medicine tracked 4,883 people under evaluation for the Framingham Heart Study. Forty years' worth of data revealed that one in four suffers from AD. Men of the same age are slightly less susceptible, having a one in six chance of AD. Combined, these risk factors threaten one out of every two older women and one in three of their male peers.

I agree with Mr. Ranganath Rao that...  Read more

I partially agree with the suggestion that villagers in India who consume mustard oil didn't have AD in old age, also because it was found in current research that turmeric and mustard oil users are less susceptible to AD, but I disagree with his query that we can't relate AD with age as we have certain data for its proof. Age is the most important known risk factor for AD. The number of people with the disease doubles every 5 years beyond age 65. Middle-aged women are at greater risk than men (AD). A recent study shows that high blood pressure dramatically increases this risk, foretelling a potential epidemic of dementia as baby boomers enter their later years. Research at Boston University School of Medicine tracked 4,883 people under evaluation for the Framingham Heart Study. Forty years' worth of data revealed that one in four suffers from AD. Men of the same age are slightly less susceptible, having a one in six chance of AD. Combined, these risk factors threaten one out of every two older women and one in three of their male peers.

I agree with Mr. Ranganath Rao that trace metals increase risk of AD, as we have with us certain data for lead-related risk of AD. Exposure to lead increases the risk for developing AD, according to a study done at Case Western University Medical School's department of neurology. Individuals in work environments with high levels of lead are three to four times as likely to have Alzheimer's as their unexposed peers later in life. The study offers the first conclusive evidence of a link between on-the-job hazards and AD. Scientists at Case Western examined the work histories of Alzheimer patients and compared them to the histories of healthy elderly people. Dr. Elisabeth Koss and her colleagues discovered that individuals with the highest levels of lead exposure were up to four times as likely to have Alzheimer's as those who had minimal work-related exposure. The research team reported their findings at the 52nd Annual Meeting of the American Academy of Neurology. Even after taking into account a number of other factors that can influence the development of the disease, results showed that 14 percent of Alzheimer patients had experienced lead exposure at work, as compared to just 6 percent of individuals without the disorder. However, no association was made between exposure to other common workplace toxins—such as aluminum, copper, iron, zinc, and solvents—and an increased risk for developing the disease. Typically, lead exposure occurs either by inhaling lead dust (the most toxic mode of transmission) or by absorbing lead through the skin. Jobs that involve smelting and casting lead, working with lead-based paints or inks, making stained glass, or manufacturing products including batteries, lead-glazed pottery, ammunition, lead pipes, and electronics parts place workers at serious risk for high lead exposure. At-home risks also exist where lead is contained in drinking water and soil, or in older homes that have peeling lead-based paint.

References:
1. Ito T, Yamadera H, Ito R, Endo S. [Effects of bright light on cognitive disturbances in Alzheimer-type dementia] Nippon Ika Daigaku Zasshi. 1999 Aug;66(4):229-38. Abstract

2. D. F. Swabb and E. Flievs., Brain Res. 1985;140:566.

3. Brusco LI, Marquez M, Cardinali DP. Monozygotic twins with Alzheimer's disease treated with melatonin: Case report. J Pineal Res. 1998 Dec;25(4):260-3. Abstract

4. Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical scale for the staging of dementia. Br J Psychiatry. 1982 Jun;140:566-72. Abstract

5. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. Am J Psychiatry. 1984 Nov;141(11):1356-64. Abstract

6. Volicer L, Harper DG, Manning BC, Goldstein R, Satlin A. Sundowning and circadian rhythms in Alzheimer's disease. Am J Psychiatry. 2001 May;158(5):704-11. Abstract

7. D. L. Bilewis and M. Hughes., J. Gerontol. A. Biol Sci. Med. Sci. 1995;50:303.

View all comments by sumit gupta

This is a very interesting finding in line with our publicaion. We have published already our finding on trace metal increase in moderately affected AD brain compared to control. In particular, we found that Zn was higher than other elements Si, Cu, Mg, Ca, Fe, Al , Fe, etc. However Fe, & Al was extremely elevated only in severe AD. Publiction is available In Alzeimr's Reports Vol 2, No. 4, 1999, pp 241-246. With regards, R.V.Rao & K.S.J.Rao et.al

View all comments by Ranganath Rao

I have a scientific question: How can aging be a risk factor for Alzheimer's? Diseases have causes, don't they?

1. Most aging humans don't get AD, and no wild animals, eating natural foods, get it, whatever their age. That includes chimps. The aging process does not cause this disease. Villagers in India who use unrefined mustard oil in their cooking do not get AD, but they age like anyone else. Sporadic AD is seen only where refined food oils are available.

2. If sporadic (non-genetic) AD takes 30-40 years to develop, then the disease must start somewhere between 30 and 40, possibly even earlier, i.e., it does not begin in old age; it begins in relatively young people, so aging may be a risk factor for the eventual outcome, but is not a factor in the origin and aetiology of the disease; AD may be time-related (slow to develop), but is clearly not age-related, in the sense that the aging process causes it.

3. Hugh Hendrie has shown that African-Americans in Indiana have 3-4 times the risk of getting AD, compared to genetically similar West Africans, so how do the...  Read more

I have a scientific question: How can aging be a risk factor for Alzheimer's? Diseases have causes, don't they?

1. Most aging humans don't get AD, and no wild animals, eating natural foods, get it, whatever their age. That includes chimps. The aging process does not cause this disease. Villagers in India who use unrefined mustard oil in their cooking do not get AD, but they age like anyone else. Sporadic AD is seen only where refined food oils are available.

2. If sporadic (non-genetic) AD takes 30-40 years to develop, then the disease must start somewhere between 30 and 40, possibly even earlier, i.e., it does not begin in old age; it begins in relatively young people, so aging may be a risk factor for the eventual outcome, but is not a factor in the origin and aetiology of the disease; AD may be time-related (slow to develop), but is clearly not age-related, in the sense that the aging process causes it.

3. Hugh Hendrie has shown that African-Americans in Indiana have 3-4 times the risk of getting AD, compared to genetically similar West Africans, so how do the latter manage to get older with much less risk of getting AD, unless they are lucky enough to avoid some dietary or toxic factor that is more common in the USA?

4. Twin discordance is common in sporadic AD; twins age at the same rate, so how come only one of them is getting AD? The most startling example of this, which triggered my investigations into diet and AD in 1990, was a discordant pair of Scottish twins, one showing plaques and tangles at autopsy, the other being completely clear of AD pathology at autopsy. Both were aging, yet only one got AD. I concluded that diet entered the picture, eventually pinning down refined, vitamin E-deficient food oils as a likely cause.

There is even suggestive evidence that sporadic AD incidence declines after the age of 90, as does the risk of breast cancer and osteoarthritis; the reason might be that most folks who were going to get these diseases have already developed them before 90, while those who are not exposed to the actual causes live on free of risk. How often do we hear of diabetes and atherosclerosis being age-related, yet there are heaps of 10-20-year-olds with type 2 diabetics in the USA, and plenty of 3-year-olds with yellow-streaked arteries!

Finally, so-called age-related macular degeneration (AMD) turns out to be mostly due to chronic dietetic deficiency of the macular pigments lutein and zeaxanthin, which are now known to improve vision, despite the person's age.

View all comments by Robert Peers

DNA Fragmentation Mechanism Involving Oxidative Stress: Relevance to Alzheimer Disease
While DNA strand breaks are stereotypical of an apoptotic program, their presence in Alzheimer disease (AD) is of such a widespread nature and numerically high scale (Su et al., 1994) that we previously argued that DNA breakage in AD did not define apoptosis and that apoptosis was unlikely to play a major role in the disease (Perry et al., 1998a,b). Supporting this, the cardinal feature of apoptosis, i.e., activation of executioner caspases, is absent in the disease (Raina et al., 2001). Therefore, rather than an apoptotic mechanism, DNA fragmentation in AD is more likely a consequence of oxidative stress (Su et al., 1997). Recently, an intriguing mechanism by which oxidative stress promotes DNA fragmentation was reported in Chemistry and Biology (Prestwich et al., 2005). Specifically, these new studies show that reactive oxygen species convert protein residues into peroxides that cleave DNA via hydrogen abstraction. Since direct oxidation of proteins is known to be an invariant...  Read more

DNA Fragmentation Mechanism Involving Oxidative Stress: Relevance to Alzheimer Disease
While DNA strand breaks are stereotypical of an apoptotic program, their presence in Alzheimer disease (AD) is of such a widespread nature and numerically high scale (Su et al., 1994) that we previously argued that DNA breakage in AD did not define apoptosis and that apoptosis was unlikely to play a major role in the disease (Perry et al., 1998a,b). Supporting this, the cardinal feature of apoptosis, i.e., activation of executioner caspases, is absent in the disease (Raina et al., 2001). Therefore, rather than an apoptotic mechanism, DNA fragmentation in AD is more likely a consequence of oxidative stress (Su et al., 1997). Recently, an intriguing mechanism by which oxidative stress promotes DNA fragmentation was reported in Chemistry and Biology (Prestwich et al., 2005). Specifically, these new studies show that reactive oxygen species convert protein residues into peroxides that cleave DNA via hydrogen abstraction. Since direct oxidation of proteins is known to be an invariant feature of AD (Smith, 1996) and is, like DNA fragmentation, widespread and chronic (Smith et al., 2002), these studies likely have great relevance to the pathogenesis of AD. Moreover, these studies should serve to further emphasize the promiscuous nature of oxidative stress that, in AD, involves damage to all of the major macromolecules of the cell (Casadesus et al., 2004) and is one of the earliest cytopathological changes in disease (Nunomura et al., 2001).

References:
Casadesus G, Smith MA, Zhu X, Aliev G, Cash AD, Honda K, Petersen RB, Perry G. Alzheimer disease: evidence for a central pathogenic role of iron-mediated reactive oxygen species. J Alzheimers Dis. 2004 Apr;6(2):165-9. Review. Abstract

Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol. 2001 Aug;60(8):759-67. Abstract

Perry G, Nunomura A, Lucassen P, Lassmann H, Smith MA. Apoptosis and Alzheimer's disease. Science. 1998a Nov 13;282(5392):1268-9. No abstract available. Abstract

Perry G, Nunomura A, Smith MA. A suicide note from Alzheimer disease neurons? Nat Med. 1998b Aug;4(8):897-8. No abstract available. Abstract

Prestwich EG, Roy MD, Rego J, Kelley SO. Oxidative DNA strand scission induced by peptides. Chem Biol. 2005 Jun;12(6):695-701. Abstract

Raina AK, Hochman A, Zhu X, Rottkamp CA, Nunomura A, Siedlak SL, Boux H, Castellani RJ, Perry G, Smith MA. Abortive apoptosis in Alzheimer's disease. Acta Neuropathol (Berl). 2001 Apr;101(4):305-10. Abstract

Smith MA, Casadesus G, Joseph JA, Perry G. Amyloid-beta and tau serve antioxidant functions in the aging and Alzheimer brain. Free Radic Biol Med. 2002 Nov 1;33(9):1194-9. Review. Abstract

Smith MA, Perry G, Richey PL, Sayre LM, Anderson VE, Beal MF, Kowall N. Oxidative damage in Alzheimer's. Nature. 1996 Jul 11;382(6587):120-1. No abstract available. Abstract

Su JH, Anderson AJ, Cummings BJ, Cotman CW. Immunohistochemical evidence for apoptosis in Alzheimer's disease. Neuroreport. 1994 Dec 20;5(18):2529-33. Abstract

Su JH, Deng G, Cotman CW. Neuronal DNA damage precedes tangle formation and is associated with up-regulation of nitrotyrosine in Alzheimer's disease brain. Brain Res. 1997 Nov 7;774(1-2):193-9. Abstract

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