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2016 Grants - Albayram
Targeting the Misshapen Pathogenic Tau Protein in Tauopathies
Onder Albayram, Ph.D.
Beth Israel Deaconess Medical Center
2016 Alzheimer’s Association Research Fellowship (AARF)
How do different modifications of the tau protein contribute to the formation of tau tangles in the brain?
In healthy nerve cells, tau protein helps to maintain cell structure and to transport nutrients throughout the cell. However, in several brain diseases, including Alzheimer’s, tau becomes abnormally modified, leading to the formation of tau tangles. Brain diseases involving tau tangles are collectively known as tauopathies. The modification of tau involves the addition of chemical phosphate groups that may promote tangle formation. Whether addition of phosphate to tau leads to tauopathy depends on where the phosphate group is attached to the tau protein.
Onder Albayram, Ph.D., and colleagues have found that addition of a phosphate group to tau at a certain position can cause tau to change shape in two different ways, known as ‘cis’ and ‘trans’. The researchers have found that cis-pTau leads to the formation of tau tangles but trans-pTau does not. The researchers have also developed a novel antibody that binds only to cis-pTau and could potentially help remove it from the brain.
Dr. Albayram and colleagues have proposed a series of studies to explore how cis-pTau may promote the formation of tau tangles throughout the brain. The researchers will isolate cis-pTau from the brains of mice as well as the brains of people who had tauopathies, including Alzheimer’s disease and chronic traumatic encephalopathy (CTE). They will expose nerve cells growing in laboratory dishes to cis-pTau and measure its effects on nerve cell function and its ability to spread from one cell to another. The researchers will also treat Alzheimer’s-like mice with their novel cis-pTau antibody to determine if it can prevent the accumulation of harmful tau and improve brain function.
These studies will provide further evidence of the molecular mechanisms that underlie the accumulation of abnormal tau protein in the brain during Alzheimer’s disease and other tauopathies. The results may also inform the development of strategies to block cis-pTau and potentially slow or halt disease progression.