Brain tissue mechanism may explain why women are more susceptible to Alzheimer's

By The Science Advisory Board staff writers

October 5, 2022 -- Case Western Reserve University researchers have identified a mechanism in brain tissue that may explain why women are twice as vulnerable to Alzheimer's disease as men. Their study, published October 4 in the journal Cell, could lead to new medicines to treat the disease.

The researchers found that women naturally express higher levels of an X-linked enzyme called ubiquitin-specific peptidase 11 (USP11). Higher USP11 levels result in greater accumulation of a protein called tau, which is responsible for the formation of toxic protein clumps inside the brain nerve cells of Alzheimer's patients.

The presence of a chemical tag called ubiquitin on tau is regulated by a balanced system of enzymes that either add or remove the ubiquitin tag. The body normally destroys unneeded tau. But when overabundant USP11 levels disrupt this process, tau may pathologically aggregate, causing nerve cell destruction and tau pathologies, or taupathies, including Alzheimer's disease.

The researchers also found that when they genetically eliminated USP11 in a mouse model, females were preferentially protected from taupathies. Their results suggest that excessive USP11 enzyme activity in females drives their increased susceptibility to Alzheimer's disease.

"We are particularly excited about this finding because it provides a basis for the development of new neuroprotective medicines," co-senior author David Kang, PhD, pathology professor at Case Western, said in a statement. "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 Alzheimer's disease."

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