Evidence found in the brain tissues of humans and mice reveals a mechanism that may explain the sex-based differences in Alzheimer's disease, including why females are more susceptible. Researchers reported in the journal Cell on October 4 that female brains show higher expression of an X chromosome-linked enzyme called deubiquitinase 11 (USP11) compared to males, leading to a greater accumulation of a protein called tau. Ubiquitin is an analytical compound found in living cells and plays a critical role in the degradation of faulty and unneeded proteins.
The study's lead author, David Kang from Case Western Reserve University, stated, "This study sets the stage for identifying other factors linked to the X chromosome that may confer increased susceptibility to tauopathy (tau-related disorders) in women." Tauopathy is known as one of the neurodegenerative diseases characterized by tau protein accumulation in neural tangles in the human brain. Tau protein clumps are a key biological hallmark of brains affected by Alzheimer's disease. Women are diagnosed with Alzheimer's at double the rate of men, and the underlying mechanism behind this gender gap has not been well understood by scientists.
One possible explanation is that women show significantly higher tau deposition in the brain. The process of eliminating excess tau begins with the addition of a chemical tag called ubiquitin to tau protein. Since dysfunction in this process can lead to abnormal accumulation of tau protein, Kang and co-author Jung A. Woo from Case Western Reserve University investigated the increased activity of the enzymatic systems that either add or remove the ubiquitin tag. They found that both female mice and humans naturally express higher levels of USP11 in the brain compared to males, and that USP11 levels are closely associated with tauopathy in females but not in males.
Furthermore, when they genetically eliminated USP11 in a mouse model of brain tauopathy, females were preferentially protected from tauopathy and cognitive impairment. Males were also protected from brain tauopathy, but not to the same extent as females. The findings suggest that excessive activity of the USP11 enzyme in females leads to their increased susceptibility to tau-related Alzheimer's disease. However, the authors caution that tauopathy-specific mouse models may not fully capture the sexual dimorphism in tauopathy that is observed in humans. Kang notes, "Regarding the implications, the good news is that USP11 is an enzyme, and enzymes can traditionally be inhibited pharmacologically. Our hope is to develop a drug that works in this way to protect women from the risk of Alzheimer's disease."
