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Uehara T, Nakamura T, Yao D, Shi ZQ, Gu Z, Ma Y, Masliah E, Nomura Y, Lipton SA. S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. Nature. 2006 May 25;441(7092):513-7. PubMed.
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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:
Prestwich EG, Roy MD, Rego J, Kelley SO. Oxidative DNA strand scission induced by peptides. Chem Biol. 2005 Jun;12(6):695-701. PubMed.
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. PubMed.
Gupta VB, Hegde ML, Rao KS. Role of protein conformational dynamics and DNA integrity in relevance to neuronal cell death in neurodegeneration. Curr Alzheimer Res. 2006 Sep;3(4):297-309. PubMed.
Hegde ML, Anitha S, Jagannatha KS. Are Monomer-Oligomer Aggregates of Amyloidogenic Peptides Toxic Species in Neurodegeneration. Neurobiol Aging 2004; 25(Suppl 2):S170.
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 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.
See also:
D. F. Swabb and E. Fliers, Brain Res. 1985;140:566.
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Bliwise DL, Hughes M, McMahon PM, Kutner N. Observed sleep/wakefulness and severity of dementia in an Alzheimer's disease special care unit. J Gerontol A Biol Sci Med Sci. 1995 Nov;50(6):M303-6. PubMed.
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