Jeremy Herskowitz, Ph.D., and his team have discovered a major advancement in Alzheimer’s disease research that could lead to new therapies to slow disease progression. Alzheimer\u2019s 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 people around the world and places a vast emotional and economic toll on families.\u00a0<\/p>\n
In Alzheimer\u2019s disease, two key proteins, extracellular amyloid-beta plaques and an intercellular protein called tau, disrupt communication between the brain\u2019s 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\u2019s disease.<\/p>\n
A\u00a0study<\/a> published in Neuron led by researchers at the\u00a0University of Alabama at Birmingham<\/a>, Rush University Medical Center in Chicago, Illinois, and SUNY Upstate Medical Center in Syracuse, New York, provides new insight into a fundamental mystery of Alzheimer\u2019s disease: how tau tangles spread from one brain region to another. The findings of the study introduce evidence that targeting tau as it spreads can offer a viable path to slowing or preventing the advancement of Alzheimer\u2019s disease.\u00a0<\/p>\n Tau is a microtubule-associated protein that is found inside the brain\u2019s neurons that helps support their internal structure by serving as a \u201cscaffolding.\u201d In people with Alzheimer\u2019s disease, 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 occurs. What remained unclear was the mechanism by which tau travels through the brain\u2019s network.\u00a0<\/p>\n \u201cSmall pieces of tau make up the aggregate inside the neuron and spread from neuron to neuron through the brain,\u201d said Jeremy Herskowitz, Ph.D., professor of neurology and neurobiology at UAB, and the Patsy W. and Charles A. Collat Professor of Neuroscience, and corresponding author of this study. \u201cNeurons are connected to each other, and they talk to each other through synapses. This would allow them to get around the brain and deposit and aggregate at different brain sections until they reach the neocortex. While that is a theory, our paper shows that is likely the mechanism of action as people age.\u201d<\/p>\n \u201cThis is a major advancement in Alzheimer\u2019s research for both therapy development and understanding how the disease works,\u201d Herskowitz said.\u00a0<\/p>\n UAB researchers identified that Alzheimer\u2019s\u2011related neurofibrillary tangles spread throughout the brain through connected neurons. Herskowitz and his team analyzed postmortem brain samples and longitudinal data from 128 participants in ROSMAP, a Rush University study involving Catholic clergy ages 65-plus who undergo annual evaluations and donate their brains after death. The participants averaged 91 years old at death, with nearly one\u2011third having Alzheimer\u2019s dementia. Gathering the fMRI and postmortem data for this research took a decade.<\/p>\n 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.\u00a0<\/p>\n The researchers integrated multiple types of information from the ROSMAP participants. First, they looked at tau seeds in both brain regions alongside each person\u2019s genetic data to determine whether tau seeds caused the formation of tau tangles. They used a method called Mendelian randomization, which helps determine cause and effect.\u00a0<\/p>\n Brain-connectivity data called antemortem functional magnetic resonance imaging, or fMRI, was used to examine each individual\u2019s unique pattern of brain wiring and evaluate whether personal wiring differences influence the number of tau seed tangles and how far the tangles spread.\u00a0<\/p>\n \u201cWe used a genetic approach called Mendelian causality to make the conclusion that the seeds generated in the temporal cortex caused the neurofibrillary tangle pathology in the neocortex,\u201d Herskowitz said. \u201cThe Mendelian causality that we used is a statistical algorithm that utilizes the genomic DNA we had from each participant, and that allowed us to make this conclusion.\u201d\u00a0\u00a0<\/p>\n 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\u2019s natural communication pathways. These pathways, or neurons, connect at synapses, which form a vast network that varies from person to person.\u00a0Tau 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\u2019s unique brain connectivity helps determine how far and how fast tau pathology advances.<\/p>\n 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\u2019s pathology.\u00a0Collectively, these findings reinforce the therapeutic potential of targeting tau seeds to slow or halt Alzheimer\u2019s disease progression.\u00a0<\/p>\n 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\u2019s success is now known.\u00a0<\/p>\n \u201cTau antibodies would stop tau from spreading from one brain region to the next,\u201d Herskowitz said. \u201cIf you stop that spreading, it would delay or prevent Alzheimer\u2019s disease dementia.\u201d<\/p>\n First author of the study, \u201cTau seeds induce neurofibrillary tangle formation across brain regions via individual specific connectivity,\u201d is Audrey Weber, Ph.D., UAB Department of Neurology. At UAB,\u00a0Neurology<\/a>\u00a0and\u00a0Neurobiology<\/a>\u00a0are departments in the\u00a0Marnix E. Heersink School of Medicine.<\/a><\/p>\n