Alzheimer's disease, cholesterol and sirtuins
The main genetic risk factor for Alzheimer's disease is associated with the SirT1 protein
LifeSciencesToday by Buck Institute: Major Alzheimer's Risk Factor Linked to Red Wine Target
The main genetic risk factor for developing Alzheimer's disease in about two-thirds of patients suffering from this disease is the cholesterol-carrying protein ApoE4, with which about a quarter of us are born. But one of the unsolved mysteries of Alzheimer's disease is exactly how ApoE4 is associated with the risk of developing this incurable neurodegenerative disease. In a study published in The Proceedings of the National Academy of Sciences (Theendakara et al., Neuroprotective Sirtuin ratio reversed by ApoE4), scientists from the Buck Institute for Research on Aging have established a link between ApoE4 and SirT1, an "anti–aging" protein that is the target of the red wine contains resveratrol substances.
Scientists have found that ApoE4 causes a sharp decrease in the level of SirT1 – one of the seven human sirtuins (sirtuins). This decrease is observed both in the culture of nerve cells and in brain samples of patients with ApoE4 and Alzheimer's disease.
"The biochemical mechanisms linking ApoE4 to Alzheimer's disease were something of a black box. However, recent research by a number of laboratories, including ours, opens this box a little," says Dale Bredesen, MD, founder and CEO of the Buck Institute, one of the leaders of the study.
In addition, the researchers concluded that disorders associated with ApoE4 and Alzheimer's disease, such as the formation of phosphorylated tau protein and beta-amyloid, can be prevented by increasing the level of SirT1, and found a number of potential drugs that interfere with the interaction of APP – ApoE.
"This study offers a new direction in the search for means of prevention and treatment of Alzheimer's disease," says senior co–author of the article Rammohan V. Rao (Rammohan V. Rao), PhD. "One of our goals is to find a safe, non–toxic drug that can be prescribed to anyone carrying the ApoE4 gene to prevent the development of Alzheimer's disease."
Dr. Rammohan and his colleagues, in particular, found that a decrease in the level of SirT1 is associated with a change in the processing of the amyloid precursor protein (amyloid precursor protein, APP). Although both ApoE3 and ApoE4 bind to ARP, only ApoE4 significantly reduces the ratio of soluble amyloid precursor protein alpha (SAPP) to beta-amyloid, suppresses the expression of SirT1, which is expressed in a significant change in the ratio of neuroprotective SirT1 to neurotoxic SirT2, is a trigger for phosphorylation of tau and ARP and induces programmed cell death – apoptosis. These data are in good agreement with the potential effects of SirT1 suppression, since overexpression of SirT1, as previously shown, enhances the expression of ADAM10, a protease that cleaves APP to form sAPP alpha and thereby prevents the formation of beta-amyloid.
The amyloid precursor protein (ARP) is cut by enzymes to form beta-amyloid,
accumulating in the form of beta-amyloid plaques in the interneuronal space. (Fig. my.science.ua )Alzheimer's disease affects 5 million people in the United States.
Drugs that can at least stop the progression of symptoms do not exist today. Preventive treatment is especially necessary for 2.5% of the population carrying two copies of the ApoE4 gene, which tenfold increase the risk of developing Alzheimer's disease, as well as 25% of the population with one copy of this gene. Scientists hope that their work will help to find simple and safe medicines that can be prescribed to ApoE4 carriers to prevent the development of Alzheimer's disease.
Portal "Eternal youth" http://vechnayamolodost.ru25.10.2013