Younger brains better than old in clearing Alzheimer’s-related protein, USF/Byrd Institute study finds

USF/Byrd neuroscientist Chad Dickey

Younger brains are more effective than older brains at getting rid of abnormal amounts of tau protein associated with Alzheimer’s disease – a mechanism that may be partly explained by a better stress response in the young, a mouse-model study led by researchers at the University of South Florida found.

The study, published this month in the American Journal of Pathology, also suggests that once some abnormal tau is produced in the brain it may interfere with the normal turnover of tau protein and lead to its destructive buildup. While normal tau helps maintain the structure of neurons, the excessive accumulation of tau leads to fibrous Alzheimer’s tangles that choke the brain’s memory center.

“We need to nail down the specifics of why the young brain can cope with high levels of tau, while the older brain cannot. This could be something like finding the fountain of youth,” said the study’s lead author Chad Dickey, PhD, a neuroscientist at the Byrd Alzheimer’s Center and Research Institute at USF. “Our results from this and previous studies suggest that targeting proteins related to stress (heat shock proteins) could benefit the treatment of Alzheimer’s disease.”

The study was done using a mice genetically engineered to develop tau protein tangles like those found in the brains of people with Alzheimer’s disease. Even though mice as young as 1 month old already had large amounts of tau in their brains, they were able to clear the protein before its abnormal accumulation took over. However, as the mice aged (6 months and 9 months), this efficient clearing of tau was somehow impaired or slowed -- a change in tau metabolism that leads to the formation of the Alzheimer’s tangles.

Heat shock proteins – proteins produced in response to fever, a toxin, heart attack or other stresses -- were absent in the youngest mice, but gradually increased with age in normal control mice. In the mice engineered to make Alzheimer’s tangles, the age-related increase in these stress proteins was accelerated, the researchers found.

“We think that stress proteins may be a double-edged sword in the brain,” said Dr. Dickey, assistant professor in the Department of Molecular Medicine. “They might help initially by fixing abnormal tau or getting rid of it, but the long-term upregulation of these proteins is likely harmful, perhaps facilitating the abnormal accumulation of tau we see in older mice.”

If further studies prove stress proteins play a role in helping younger brains effectively clear excessive tau, researchers may be able to develop a new treatment by harnessing that early mechanism for older brains, said study co-author David Morgan, PhD, professor of molecular pharmacology and physiology at USF.

Tau is one of two types of proteins considered hallmarks of Alzheimer’s disease. For decades scientists have focused on the other Alzheimer’s-related protein, amyloid beta, which forms destructive clumps outside the nerve cells before the balance of tau is disrupted inside the nerve cells. The two are likely inextricably connected, so that a workable treatment for Alzheimer’s will require battling the disease on both fronts.

Dr. Morgan says a closer examination of tau pathology is the next wave in Alzheimer’s research. “By the time someone shows symptoms of Alzheimer’s disease, the neurofibrillary tau tangles could already be taking root in the brain. If that’s the case, it may be too late for a treatment targeting amyloid alone to work,” he said. “Tau therapy is an alternative approach likely to be more effective later in the disease.”

USF collaborated with researchers from the Mayo Clinic in Jacksonville, FL, the University of London Institute of Neurology, and Northwestern University in Chicago. The study was supported by the National Institute on Aging, Alzheimer’s Association, CurePSP, National Institute of Neurological Disorders and Stroke, and the Reta Lila Weston Trust for Medical Research.

- Story by Anne DeLotto Baier, USF Health Communications
- Photo by Eric Younghans, USF Health Communications/Media Center