New research suggests that scientists have discovered the “Big Bang” of Alzheimer’s disease – the exact point a healthy protein in the brain turns toxic and clumps together to create the characteristic tangles found in the brains of Alzheimer’s patients.
A new study from researchers from UT Southwestern’s O’Donnell Brain Institute has given novel insight into the changing shape of the tau protein molecules just before they begin to stick together to form large aggregates. This study gives new strategies to detect and prevent Alzheimer’s by stabilizing the tau proteins before they start to change shape.
Tau proteins, first named by Mac Kirshner in 1975, are a kind of protein found in the brain that assists with the assembling of microtubules in cells. The protein is largely found in the axons of neurons, and also plays a role in cell differentiation and cell polarization. Unhealthy tau proteins stop performing this function and begin to stick together, forming large clusters around neurons. The presence of these clusters is associated with a wide variety of neurodegenerative diseases, including Alzheimer’s.
According to this study, tau protein aggregation is due to small changes in the monomer structure of the tau molecule. Scientists isolated two samples of tau proteins, one from the brains of healthy patients, and one from the brains of those afflicted by Alzheimer’s. The toxic variety of tau was separated from other varieties by the use of special cells, grown specifically to react to the toxic form of tau. By using mass spectrometry to detect changes in the molecular structure of the protein, scientists found that the harmful form of the tau protein changes shape to expose a part of itself that is normally folded inside. The exposed part causes the molecule to stick to other tau molecules like little Lego blocks, thus creating the characteristic clumps that essentially strangle healthy neurons.
Pathologists have long known that tau aggregation is related to neural degeneration. The accumulation of tau molecules blocks essential nutrients from reaching cells in the brain, causing those cells to die. But until now, they have not had a clear understanding of the mechanism underlying the aggregation process. Now, they have strong evidence for a mechanism that explain why tau molecules start to aggregate in the way that they do.
The study, which can be read in full at eLife, undercuts a previous assumption about the physical shape of tau proteins. Previous thought held tau proteins to be intrinsically unstructured; that is, lacking any determinate three-dimensional order. Instead, the research provides evidence that some tau proteins do in fact have a kind of ordered structure. Some proteins can become unfolded, and expose an inner portion. The malformed tau protein then functions as a kind of scaffolding or skeleton for aggregate formation.
This finding suggests a different origin for tau aggregation than other views in the literature. Other views hold that tau aggregation is initiated by the formation of “tau droplets,” a gel like substance that is created by the hyperphosphorylization of tau proteins. These tau droplets then act like glue and aggregates form around these pockets of gel.
The study gives strong evidence that there are actually at least two distinct configurations of tau molecules. One set, which researchers called Mi, is relatively inert and represents the majority of tau proteins. The other set, termed Ms, shows an inherent disposition to self-assemble. These self assembling proteins act as a template and initiator for fibral growth. Among the set Ms are various monomic substructures which explain how a single tau protein may assemble into structurally diverse amyloid strains. These diverse amyloid strains could each be responsible for a number of different kinds of dementias, such as Parkinson’s disease. The study clarifies that the distinction between “seed-competent” and “inert” forms of tau do not refer to different chemical types, but to “multiple structural ensembles separated by defined energy and/or kinetic barriers.” In essence, “seed-competent” and “inert” forms refer to functional groups of protein, and there very well may be many intermediate forms between the two families of proteins. These different functional groups could go towards explaining different types of neurodegenerative conditions.
For the first time, scientists have a window into the potential molecular genesis of Alzheimer’s disease. Although it is not known exactly what causes one species of the tau protein to morph into the harmful variant, it is believed this transition marks a critical point in the progression of the disease. “This is a way of peering to the very beginning of the disease process,” said Dr. Diamond, one of the leading researcher on the team. “It moves us backward to a very discreet point where we see the appearance of the first molecular change that leads to neurodegeneration in Alzheimer’s.”
Despite billions in research and trials, Alzheimer’s is still a devastating disease in the world. Alzheimer’s Disease International cites the estimated number of those afflicted worldwide at 50 million as of 2017, with that number predicted to double every 20 years. A large fraction of those cases occur in impoverished areas where adequate medical care is either unavailable or hard to come by. In addition, the estimated total economic impact of Alzheimer’s related dementia is over 800 billion USD annually, a number which is predicted to be in the trillions by 2019.
The team is hopeful that these new findings will turn the tide in the battle, as identifying the molecular genesis of the neurodegenerative process provides a clear marker for early diagnosis, before memory loss and cognitive decline significantly manifest. By identifying the disease early, it is hoped that aggressive treatment could slow the neurodegeneration. Ideally, research will eventually pinpoint a way to reverse the shape shifting of the proteins, which could function as an effective cure for the disease.
“The hunt is on to build on this finding and make a treatment that blocks the neurodegenerative process where it begins,” Dr. Diamond said. “If it works, the incidence of Alzheimer’s disease could be substantially reduced. That would be amazing.”
The next step in the team’s research involves developing a clinical test that can detect the first signs of the protein in a patient’s blood or spinal fluid. In addition, recent clinical success for treating heart failure with the new drug Trafamidis, which works by stabilizing the shape of the protein transthyretin, gives researchers hope that a similar treatment can be developed to stabilize the shape of tau proteins. For now though, this new finding could represent the first step towards research for an effective treatment.
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