Study reveals how tau tangles spread from one brain region to another in Alzheimer's

Alzheimer's disease is a progressive neurodegenerative disorder that slowly impairs memory, affects thinking skills, and eventually interferes with daily functioning. It is the most common cause of dementia, which affects millions of families around the world and places a vast emotional and economic toll on families.

In Alzheimer's disease, two key proteins, extracellular amyloid-beta plaques and an intercellular protein called tau, disrupt communication between the brain's cells and lead to cell damage and death. As tau becomes abnormal it forms neurofibrillary tangles and spreads through critical regions of the brain, triggering cell death and the cognitive decline characteristic of Alzheimer's disease.

Tau is a microtubule-associated protein that is found inside the brain's neurons that helps support their internal structure by serving as a "scaffolding." In people with Alzheimer's disease, however, tau proteins begin sticking together inside cells. These tangles clump together and impair neural function, which eventually kills the cells. The more that tau spreads, the more memory loss that occurs. What remained unclear was the mechanism by which tau travels through the brain's network.

"This is a major advancement in Alzheimer's research for both therapy development and understanding how the disease works," said Herskowitz.

Herskowitz and his team analyzed postmortem brain samples and longitudinal data from 128 ROSMAP participants, a Rush University study involving Catholic clergy ages 65+ who undergo annual evaluations and donate their brains after death. The participants averaged 91 years old at death, with nearly one‑third having Alzheimer's dementia. Gathering the fMRI and postmortem data for this research took a decade.

Researchers examined two brain samples from each participant. One sample was from the lower temporal lobe, which is vital for memory recall. The second was from the upper frontal lobe, which supports working memory and complex thought. Tau typically begins accumulating in the temporal lobe before spreading to the frontal lobe. This progression mirrors the shift from early memory problems to more advanced cognitive decline.

The researchers integrated multiple types of information from the ROSMAP participants. First, they looked at tau seeds in both brain regions alongside each person's genetic data to determine if tau seeds caused the formation of tau tangles. They used a method called Mendelian randomization, which helps determine cause and effect.

Brain-connectivity data called antemortem functional magnetic resonance imaging (fMRI) was used to examine each individual's unique pattern of brain wiring and evaluate whether personal wiring differences influence the amount of tau seed tangles and how far the tangles spread.

"We used a genetic approach called Mendelian Causality to make the conclusion that the seeds that were generated in the temporal cortex caused the neurofibrillary tangle pathology in the neocortex. The Mendelian causality that we used is a statistical algorithm that utilizes the genomic DNA that we had from each participant, and that allowed us to make this conclusion," said Herskowitz.

This study represents the largest investigation of tau seed bioactivity in human brains to date, which has never been paired with fMRI data. Overall results indicate significant findings. The researchers discovered that tau seeds could spread primarily along an individual's natural communication pathways. These pathways, neurons, connect at synapses which form a vast network that varies from person to person. Tau seeds appear to travel along these pathways, moving from one synapse to the next and seeding new tangles as they go. In short, an individual's unique brain connectivity helps determine how far and how fast tau pathology advances.

While future research is necessary to fully explore the specific mechanisms used by tau seeds to spread across the cerebral cortex through synapses, the study clearly demonstrates that personal differences in neuronal wiring influence the spread of Alzheimer's pathology. Collectively, these findings reinforce the therapeutic potential of targeting tau seeds to slow or halt Alzheimer's disease progression.

Previous clinical trials have shown that tau traveling outside of the cell has been susceptible to being targeted by therapeutic antibodies. With these novel research findings, the reason for the antibody's success is now known.

"Tau antibodies would stop tau from spreading from one brain region to the next. If you stop that spreading, it would delay or prevent Alzheimer's disease dementia," said Herskowitz.

First author of the study "Tau seeds induce neurofibrillary tangle formation across brain regions via individual specific connectivity" is Audrey Weber, Ph.D., UAB Department of Neurology. At UAB, neurology and neurobiology are departments in the Heersink School of Medicine.

Other authors of the study are Kelsey M. Greathouse, UAB Department of Neurology and Center for Neurodegeneration and Experimental Therapies; David A. Bennett and Shinya Tasaki, Rush University Medical Center; and Chris Gaiteri, and Bernard Ng, Rush University Medical Center and SUNY Upstate Medical University.

Support came from National Institutes of Health grants F99AG083305, T32NS095775, R21AG085379, P30AG086401, R01AG061800, R01AG061798, R01AG057911, U01AG079847, P30AG10161, P30AG72975, R01AG15819, R01AG17917, U01AG46152, U01AG61356.

Source:

University of Alabama at Birmingham

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