Finding of dementia genes could speed drug discovery in Alzheimer’s and other brain disorders

Brain
Two gene clusters are associated with mutations that cause the overproduction of tau, UCLA researchers discovered. (VSRao/Pixabay)

The overproduction of a protein called tau has long been observed in the neuron degeneration that causes Alzheimer’s and other forms of dementia. But the exact genetic process that causes tau to proliferate has been something of a mystery.

Scientists led by the University of California, Los Angeles, say they’re a step closer to understanding the genes involved in the overproduction of tau. They believe their findings could improve efforts to develop treatments for Alzheimer’s, early-onset dementia and other brain diseases.

The team found two gene clusters beset by mutations that cause an overproduction of tau. They reported their findings in the journal Nature Medicine.

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Drug developers targeting Alzheimer’s and other forms of dementia have been focused on tau and another protein, beta-amyloid, but their efforts have been largely unsuccessful. Even when an anti-amyloid drug under development by Biogen and Eisai showed promise over the summer in slowing Alzheimer’s, several experts questioned the results, because only the highest dose seemed to show cognitive benefits

In scrutinizing tau, the UCLA researchers focused on a type of early-onset dementia called frontotemporal dementia. They started with a “systems biology” approach—using analytical tools to study the interactions between thousands of genes, cells and proteins. Once they identified the two gene clusters, they studied the mutations in three different strains of mice, observing abnormal genetic activity in the brain at different points of time.

That allowed them to confirm that the events leading to the death of brain cells are confined to the two gene clusters they had identified.

Other research teams have made some inroads in their efforts to determine tau’s role in dementia. In September, for example, scientists led by Massachusetts General Hospital and Johns Hopkins said they used brain tissue from Alzheimer’s patients to discover that tau impairs a key membrane in the brain. That in turn disrupts the exchange of proteins and RNA, which can cause tau to build up even more, they determined.

The UCLA team says more work needs to be done to identify the proper drug targets for lowering tau. But the researchers believe their findings provide “an important roadmap for the development of potentially effective new drugs for Alzheimer's disease and other dementia,” said senior author Daniel Geschwind, M.D., Ph.D., a professor of neurology and psychiatry at UCLA’s David Geffen School of Medicine.