ApoE4, a cholesterol-carrying protein, is, at least in part, responsible for the development of Alzheimer’s disease (AD) in around two-thirds of individuals who develop this disease. However, it is not known how ApoE4 is involved in generating AD. Researchers at the Buck Institute (San Francisco), assisted by several other researchers, including Dr. Matthew Hart of the University of Texas Health Science Center, have discovered a connection between ApoE4 and SirT1 that is targeted by resveratrol, a powerful antioxidant that is present in red wine. SirT1 is known as an anti-aging protein. The current study is available in The Proceedings of the National Academy of Sciences.
Lead scientists in the study Rammoham Rao, PhD, and Dale Bredesen, MD, founding CEO of the Buck Institute, have uncovered that ApoE4 generates a significant decrease in SirT1. This result was found in cultured neurons as well as brain samples from patients with ApoE4 and AD. They also discovered that abnormalities linked with ApoE4 and AD, for example production of phospho-tau and amyloid-beta, could be prevented by increasing SirT1. Additionally, the researchers have identified drugs that exert the same effect. Rao believes that this research offers a way to not only screen for Alzheimer’s disease but provide a way to prevent and treat this neurodegenerative disease. “One of our goals is to identify a safe, non-toxic treatment that could be given to anyone who carries the ApoE4 gene to prevent the development of AD.”
The reduction in SirT1 was found to be associated with the way amyloid precursor protein (APP) is processed. The ApoE4 protein favors formation of amyloid-beta peptide. Amyloid-beta is known to be linked to sticky plaques that are the visual marker of AD. With ApoE3, which imparts no increased risk of Alzheimer’s, there was a greater ratio of the anti-Alzheimer’s peptide (sAPP) present relative to the pro-Alzheimer’s amyloid-beta peptide. This result supports what happens with a reduction in SirT1. Previous experiments demonstrated that an increase in SirT1 increases ADAM10 which is an enzyme that cleaves APP to make sAPP alpha and prevent amyloid-beta.
It is reported that Alzheimer’s disease affects more than 5 million Americans. Currently, there is no cure or any way to stop the progression of symptoms such as memory loss. It is desirable to find preventative therapies, especially for 2.5 percent of the population that carry two alleles for ApoE4. Carrying two alleles puts an individual at a 10-fold increased risk of developing AD. Additionally, 25 percent of the population carries a single copy of ApoE4, which also confers risk. The Buck researchers hope that the current study will identify therapies that will prevent AD.