Washington: Researchers including an Indian-origin scientist have discovered a link between ApoE4 and SirT1, an "anti-aging protein" targeted by resveratrol, present in red wine.
The major genetic risk factor for Alzheimer's disease (AD), present in about two-thirds of people who develop the disease, is ApoE4, the cholesterol-carrying protein that about a quarter of us are born with. But one of the unsolved mysteries of AD is how ApoE4 causes the risk for the incurable, neurodegenerative disease.
The Buck researchers found that ApoE4 causes a dramatic reduction in SirT1, which is one of seven human Sirtuins.
Lead scientists Rammohan Rao, PhD, and Dale Bredesen, MD, founding CEO of the Buck Institute, say the reduction was found both in cultured neural cells and in brain samples from patients with ApoE4 and AD.
The Buck group also found that the abnormalities associated with ApoE4 and AD, such as the creation of phospho-tau and amyloid-beta, could be prevented by increasing SirT1. They have identified drug candidates that exert the same effect.
In particular, the researchers discovered that the reduction in SirT1 was associated with a change in the way the amyloid precursor protein (APP) is processed.
Rao said that ApoE4 favoured the formation of the amyloid-beta peptide that is associated with the sticky plaques that are one of the hallmarks of the disease. He said with ApoE3 (which confers no increased risk of AD), there was a higher ratio of the anti-Alzheimer's peptide, sAPP alpha, produced, in comparison to the pro-Alzheimer's amyloid-beta peptide.
This finding fits very well with the reduction in SirT1, since over expressing SirT1 has previously been shown to increase ADAM10, the protease that cleaves APP to produce sAPP alpha and prevent amyloid-beta.
The study has been published in The Proceedings of the National Academy of Sciences.