Alzheimer’s disease (AD) is the most common neurodegenerative disease, at present still incurable. According to statistics published by the World Health Organization (WHO), more than 50 million people worldwide currently suffer from the disease. By 2050, the number of sufferers is expected to triple, reaching 152 million patients.
Typical symptoms include memory impairment, disorientation, language impairment, impaired concentration and attention, delusions and hallucinations, and a variety of mood and behavioral changes, the effects of which are devastating and life-altering for both patients and their families. The likelihood of developing Alzheimer’s disease increases dramatically with age.
Although it is widely recognized that susceptibility to Alzheimer’s disease is higher among older adults and those with a family history of the disease, a lesser-known risk factor is gender. The vast majority, 2/3, of this group are women. After age 65, 1 in 6 women versus 1 in 11 men will develop this type of dementia. And while gender differences in the distribution of sufferers are significant and knowledge of the disease continues to grow, it remains unclear why it is women who are more likely to develop Alzheimer’s disease. Moreover, gender differences also affect the clinical features of the disease: much more severe pathology and faster rates of brain atrophy have been observed in women than in men.
How the disease develops has never been fully explained. It is likely that molecular defects in brain cells, involving among other things the so-called tau proteins, play a key role. In healthy neurons, the tau protein stabilizes microtubules that help move nutrients from the nerve cell to the axon and dendrites. In patients with Alzheimer’s disease, unusual chemical changes cause tau proteins to detach from microtubules and attach to other tau molecules, forming thread-like chains that come together to form tangles inside neurons, called neurofibrils (or neurofibrillary tangles). This causes microtubules to become disoriented, damaging the transport system in neurons. And this in turn damages synaptic communication, or the transfer of information between neurons, and ultimately disrupts the function of brain cells.
In their study, researchers at the Center for Systems Biomedicine at the University of Luxembourg looked for molecular differences between the sexes that might contribute to differences in the frequency and characteristics of the disease. They analyzed thousands of samples from the brains of about 650 deceased people of both sexes, some of whom were affected by the disease and others who were not.
The team of researchers identified the USP9 (ubiquitin-specific peptidase 9) gene and showed that it has different properties in men and women with Alzheimer’s disease. The USP9 gene appears to provide protection against the disease in men by interacting with another gene that in turn helps regulate the microtubule-associated protein tau (MAPT).
The tau protein is a protein that is present in the normally functioning brain, but is found at higher levels in the Alzheimer’s brain. To discover how USP9 works and to link its role to the function of tau protein in Alzheimer’s disease, the researchers examined the gene in cell cultures and also conducted experiments with Danio brindle, a freshwater fish in the carp family.
The study showed that inactivation of USP9 significantly reduces tau gene activity in both models. The USP9 gene may therefore be a target for new therapies, even if the road to developing possible drugs against Alzheimer’s disease is still long.
To better understand the molecular signaling chain that links USP9 and MAPT, the researchers developed a computer model that combines measured data with regulatory information known from the literature and public databases.
They found that proteins that have previously been suggested as potential drug targets in Alzheimer’s disease may also be affected by USP9. Thus, USP9 may have a significant impact as a pharmacological target protein.
