What was the motivation for your research study?
In the brain, there is an important protein called tau that helps maintain the proper structure of nerve cells. When a particular tau protein is no longer needed for its nerve cell’s function, however, it is normally designated for destruction and clearance. Sometimes this clearance process is disrupted, which causes tau to pathologically aggregate inside nerve cells. This leads to nerve cell destruction in conditions called tauopathies, the most well-known of which is Alzheimer’s disease (AD). The process of eliminating excess tau begins with the addition of a chemical tag called ubiquitin to the tau protein. The presence of ubiquitin on tau is regulated by a balanced system of enzymes that either add or remove the ubiquitin tag. Since dysfunction of this balanced process can lead to abnormal accumulation of tau in AD, we searched for reasons why this might happen. Specifically, we looked for increased activity of the enzymatic system controlling the removal of the ubiquitin tag, since over-activation of this side of the balance could lead to pathological tau accumulation. We reasoned that if this could be identified, then it could provide a basis for the development of new medicine that could restore the proper balance of tau levels in the brain.
What is the significance of these findings in simple terms?
The major significance of our study is that through an unbiased discovery approach, we discovered that the USP11 enzyme confers greater vulnerability to AD in women by causing abnormally high tau aggregation in their brains. It has long been recognized that about twice as many women as men are affected by AD, and also that women display higher levels of tau aggregation in the brain than men. However, the reason for this has been a mystery. Now, we have found that both female mice and human women naturally express higher levels of USP11 in the brain than males, and also that USP11 levels correlate strongly with brain tau pathology in females but not males. Furthermore, when we genetically eliminated USP11 in a mouse model of brain tau pathology, females were preferentially protected from tau pathology and cognitive impairment. Males were also protected against tau pathology in the brain but not nearly to the extent as in females. Thus, we can conclude that excessive activity of the USP11 enzyme in females drives their increased susceptibility to tau pathology in AD.
What are the implications?
In terms of implications, the good news is that USP11 is an enzyme, and enzymes can traditionally be inhibited pharmacologically. Our hope is to develop a medicine that works in this way, in order to protect women from the higher risk of developing AD.
What would you hope our readers might take away from these findings, and what should they NOT take away?
So, the takeaway message from this study is that we now understand one significant reason why women are generally more vulnerable to AD than men. Armed with this knowledge, the field can now address this problem from a novel perspective. This is not to say that USP11 is the only cause for heightened AD susceptibility in women. Indeed, there are other known and unknown factors that contribute to this effect. However, we are particularly excited about this finding because it provides a basis for the development of new neuroprotective medicines.
Can you describe in simple terms how this research study is novel?
The novelty of our study resides in the discovery that excessive USP11 enzyme level in the brains of women causes the removal of too many ubiquitin tags from tau, which prevents the normal elimination of tau from nerve cells. When excess tau is not eliminated, it forms pathological aggregates that contribute to AD. Our data show that women experience this more than men because the gene for USP11 resides on the X chromosome. Women have two X chromosomes, while men only have one. Although large parts of the extra X chromosome in women are normally inactivated, this is far from a complete process. Indeed, the amount of X-chromosome inactivation varies across women and even across cells within the same woman. As a result, various parts of the extra X chromosome remain active in any given cell, such that the genes encoded by those parts of the X chromosome are expressed at higher than normal levels. This is very likely why women have higher levels of USP11 in their brains than men, and as a result, do not eliminate tau at the same rate as men.
Were you especially surprised by anything you found? Was there anything else that you found particularly notable about your findings, or anything else in general you’d like to add?
We performed an unbiased screen simply to identify enzymes that could remove ubiquitin from tau, and we were not expecting to find a cause for increased AD vulnerability in women. Our study evolved in this exciting direction, however, when we realized that USP11 is located on the X chromosome and that even nondementia females show physiologically increased USP11 levels in the brain. Another exciting result was that the removal of ubiquitin from tau by USP11 creates the necessary space on tau to allow another modification to occur, called acetylation. Previous studies have shown that acetylated tau is more prone to aggregation and is increased in AD and after traumatic brain injury. In this study, we found that USP11 not only reduces tau elimination but also increases tau aggregation by increasing its acetylation.
What are the limitations of this research study?
This study provides a significant explanation for the increased vulnerability of women to AD through increased tau aggregation in the brain. However, another major aspect of brain pathology in AD is amyloid plaques, which have also been shown to be more extensive in women than in men. We did not specifically study brain amyloid plaque pathology in our current study, and this could be another avenue for understanding why AD is more prevalent and aggressive in women than in men.
How might these findings be put to use? What could be the impact of this study?
Like all enzymes, USP11 can be pharmacologically inhibited by drugs. Our hope is that academic laboratories and the pharmaceutical industry will take this opportunity to develop drugs that specifically inhibit USP11 activity. This could also come in the form of screening whether any existing FDA-approved drugs might happen to unexpectedly inhibit USP11. Based on the results of our study, we predict that USP11-inhibiting drugs will protect women from developing the accelerated tau pathology that they exhibit relative to men.
What is your future plan for following up on this study? Where is this research heading next? What do you plan to do with this information?
In addition to looking for ways to develop a medicine based on our results, we are also studying how this process affects downstream aspects of tau pathology in the brain. For example, we know that tau pathology spreads from nerve cell to nerve cell through interconnected regions of the brain. We are currently studying whether the modifications on the tau protein made by USP11 alter, and perhaps accelerate, the spreading of pathological tau throughout the brain. We are also investigating the possible connection between brain amyloid plaques and USP11.