UNC researchers discover a protein cascade that helps piece together the biochemical signals of Alzheimer's disease.
How UNC's new research helps connect mysterious signals of Alzheimer's
September 26, 2017
As we make progress in the fights against cancer, heart disease and infectious diseases here in the United States, the burden of Alzheimer’s and other dementias is increasing. By 2050, more than 16 million Americans could be living with Alzheimer’s disease, and this could cost Americans more than $1 trillion.
Alzheimer’s is currently a disease without a cure and until one is found, that tremendous cost goes mainly to managing the symptoms and providing assistance for those affected by the disease. The trouble is that while scientists know what Alzheimer’s looks like on a molecular level, when the brain shows symptoms and even before, the process by which the brain's proteins form the plaques and tangles associated with Alzheimer’s is still a mystery.
Researchers from the UNC School of Medicine, however, may have unraveled a large piece of that process. Using cells in a petri dish, they showed how amyloid beta plaques, tangled tau proteins and inflammation feed into each other to create the molecular environment found in Alzheimer’s disease.
Not only does the study, published in the journal Cell Reports show that mechanism, it also shows why some current Alzheimer’s treatments have been found to be effective in combatting the disease’s symptoms.
The signatures of Alzheimer’s are large clumps, called ‘plaques’ made of protein pieces called beta-amyloid and tangles of stabilizing molecules called tau proteins that disrupt how the brain transfers electrical impulses. More recently, scientists have found that brains with Alzheimer’s are soaked in a solution of inflammatory compounds, and that fighting inflammation is associated with reduced risk of Alzheimer’s disease.
The trouble is, neuroscientists have not known exactly how these three major biochemical markers arise and influence each other to create the debilitating symptoms of Alzheimer’s disease.
Todd Cohen, lead author of the study and assistant professor of neurology at UNC, exposed nervous tissue to small beta-amyloid fragments, the goal being to induce an inflammatory response in the tissue consistent with that of Alzheimer’s disease. Small conglomerates of amyloid beta are considered to be the most dangerous as they fit in the spaces where brain cells communicate with each other and block the signals passing between them.
The amyloid triggered an inflammatory response, causing the fluid surrounding the brain cells to become filled with small inflammatory protein fragments. The researchers then soaked brain cells in that same inflammation-filled fluid, and the cells began to develop tiny bead structures on the ends they use to communicate. These bead structures were filled with large amounts of mutated tau protein, as well as calcium, which can harm brain cells. These beads have been seen in Alzheimer’s patients as an early sign of physical brain damage, making a strong case for a scenario in which amyloid triggers inflammation, which causes tau and calcium beads to form in brain cells.
Further, the researchers explored the specific proteins and protein fragments that facilitate the beading. One of those fragments, MMP-9, can cause massive calcium influxes, and is known to be released in the presence of beta-amyloid. Another, called HDAC6 shows up within the beads, and though its purpose is to grab unwanted protein clumps and dispose of them, it actually plays a role in clumping those tau proteins within the beads.
Both proteins have been found in Alzheimer’s patients and drugs that inhibit HDAC9 have already shown promise in combatting the disease. This study helps explain why those drugs are as effective as they are.
While this study does seem to answer some long-standing questions with about how Alzheimer’s occurs, there are still a few unknowns. First, while abnormal tau proteins are present in both the lab experiments of this study and Alzheimer’s patients, they are not the same abnormal form. Cohen and his colleagues think the form found in this study could be the way tau protein gets started on the path to Alzheimer’s, but to prove that, they would need to show the evolution from one form to the other.
Second, these experiments were performed on cells in a petri dish, which is close, but not quite the same as seeing the same results in a live human brain. The researchers are currently working on a mouse model that the researchers can use to investigate these findings, but even that could be years away.
Still, as the burden of Alzheimer’s and other dementia grows, having a thorough understanding of the origins of disease could allow for treatment, early detection and even prevention of some of the most debilitating conditions known to man.
Daniel Lane convers science, medicine, engineering and the environment in North Carolina.