On 22 June, Dr. Simon Dujardin and colleagues published an article in Nature Medicine, describing striking differences in Tau biochemistry between individuals with Alzheimer’s disease, and identifying particularly hazardous forms of soluble Tau that may be associated with a more rapid disease course.
The clinical course that Alzheimer’s disease (AD) follows is extremely heterogeneous, with wide-ranging rates of disease onset and cognitive decline. Tau, a microtubule-associated protein that accumulates in neurofibrillary tangles during the development of AD, also exists in soluble and hyperphosphorylated forms. Several lines of evidence have shown that soluble Tau oligomers are neurotoxic, causing degeneration and death of brain cells. In their paper, Dr. Dujardin and colleagues set out to establish whether differences in Tau biochemistry could explain why some individuals experience a particularly rapid and severe Alzheimer’s disease course compared to others.
To investigate Tau biochemical diversity in AD, the researchers obtained postmortem brain samples from 32 participants in the Massachusetts Alzheimer’s Disease Research Center Longitudinal Cohort Study. Each of these participants had a confirmed AD diagnosis, with detailed information on their clinical progression over time. Using soluble extracts prepared from the brain samples, the researchers found substantial between-participant differences in the ability of Tau to propagate from cell to cell, seeding new Tau aggregates. They then performed biochemical assays to identify the Tau characteristics that drive higher versus lower seeding; these analyses suggested that oligomeric, phosphorylated Tau forms had higher levels of seeding compared to other forms. More detailed analyses revealed specific Tau phosphorylation sites that correlated with higher or lower seeding ability, suggesting that Tau phosphorylation greatly impacts on its ability to seed.
Finally, they looked at whether the rate of clinical decline was linked to the biochemical properties of brain extract Tau. Interestingly, they found that higher rates of Tau seeding were associated with more rapid clinical decline, and younger age of AD onset. High seeding was particularly prevalent in participants who carried twoApoE4alleles, pointing to a role for genetic risk factors in influencing Tau aggregation and seeding.
The original article can be found here: https://www.nature.com/articles/s41591-020-0938-9#Abs1