New Hope for Alzheimer’s By Preventing Tau’s Spread in the Brain
A BrightFocus-funded research team has brought us closer to the possibility of a vaccine to help rid the brain of toxic tau—and possibly keep it from spreading—in Alzheimer’s disease (AD).
Results of in vitro experiments, performed in their lab, have shown that monoclonal antibodies they’ve developed are capable of disarming the harmful effects of abnormal tau protein. Monoclonal antibodies are drugs bioengineered to mimic natural antibodies, only with slight differences that allow them to detect and bind to specific cells or molecular formations in the body. In that way they work to block or instigate the body’s own biochemical responses.
In these researchers’ experiments, the antibodies were designed to target abnormal tau that’s been released from neurons, where it normally lives and performs a useful function, into extracellular space, where it collects in fibrous formations known as “tau tangles.” It’s believed that in addition to disrupting neuronal function, this misshapen, extracellular tau also may act in prion-like fashion to “seed” the spread of Alzheimer’s in the brain.
The work was directly supported by a 2013-16 BrightFocus grant to Kristen Funk, PhD, at Washington University in St. Louis (WUSTL), who served as first author on a report in the August 28 issue of the Journal of Biological Chemistry. Results showed that the three antibodies they’ve developed worked in more than one way to arrest tau: by promoting it’s clearance via microglia (the brain’s resident immune cells), and by blocking uptake of diseased tau by neurons.
Protein Misfolding, Tauopathy, and the Prion Hypothesis
Tau amyloid and beta amyloid (Aβ), both associated with Alzheimer’s are among an estimated 50,000-some proteins in the human body. Considered the “building blocks” of life, proteins are made up of amino acid molecules that have been strung together, and which have a remarkable ability to assume different molecular shapes. By doing so, they can exert a diverse array of physical and chemical properties.
The shape of a protein is controlled by a process known as “folding,” which refers to the way each protein configures itself into a three-dimensional structure from a string of molecules. In the case of “abnormal” tau, a protein gone bad, repetitive misfolding causes it to devolve from its normal tubular structure, which helps stabilize a transport system for neurons, into the neurofibrillary tau tangles seen in Alzheimer’s disease.
Decades ago, Nobel Laureate Stanley Prusiner, PhD, was the first to show that certain misfolded proteins, which he named “prions,” have the ability to replicate and spread. He won the Nobel Prize for this discovery in 1997.
Then in 2009, Diamond, while at WUSTL, made the discovery that tau misfolds into several different shapes in a test tube, affecting nearby cells. That discovery led him and others to suspect that diseased tau had prion-like properties. They reasoned it might lie behind recognized tauopathies, and might possibly serve as a root cause of the brain’s pathologic changes with Alzheimer’s.
Investigating further, Diamond found that when cells infected with misshapen tau reproduced, their offspring contained copies of tau misfolded in the same fashion as the parent cell. “Further, if we extracted the tau from an affected cell, we could reintroduce it to a naïve cell, where it would recreate the same aggregate shape,” Diamond said at the time.
These results, which were directly supported though BrightFocus’ 2010-13 grant to Diamond, were corroborated at successively higher levels: in the test tube, in animal models, and in autopsied human brains of Alzheimer’s patients, where the same tau prion strains were identified. Last year Diamond published these findings in Neuron [see our Science News report], and that helped bring back Prusiner’s “prion hypothesis” as a credible explanation for how Alzheimer’s might spread.
Engineering Ways to Stop Tau’s Spread
Funk meanwhile, focused her energies on ways to compartmentalize and contain tau’s spread in the Alzheimer’s brain.
“We, and others, saw that antibodies against tau protein reduced the development of pathology in animal models of disease; however it was unclear how this was working,” she said in a recent interview. “That’s because, in contrast to Aβ, which aggregates outside of the cell, tau aggregates inside the cell. It is generally accepted that antibodies cannot enter the cell, so it was unclear how these antibodies were exerting their effect.”
And even though she wasn’t directly involved with Diamond’s investigation into tau’s prion-like properties, “our study does build on it, and really tested that hypothesis,” Funk said.
“The prion hypothesis provides a mechanism by which the antibodies might be effective, ie, that the antibodies exert their effect on the extracellular tau that has been released.
Of the three specific anti-tau monoclonal antibodies she and her team have developed so far, two were shown to promote uptake and clearance of abnormal tau via microglia, which are host defense cells in the brain. A third antibody was shown to block uptake of abnormal, AD-derived tau into neurons.
The work is tremendously important as a “proof of concept,” showing not only that anti-tau therapy is effective, but could work in multiple ways. Up ahead, future studies are needed to clarify the respective importance of the two different mechanisms that have been documented so far, and how effective each is in stopping tau’s spread. The team also will continue the search for additional antibodies.
In a Q & A interview below, Diamond speculates that it could take less than a decade before these newly discovered anti-tau antibodies might become available in the form of a vaccine approved to treat Alzheimer’s.
Q/A with BrightFocus Researchers Kristen Funk and Marc Diamond
Q. With funding from BrightFocus (and others), the Diamond lab gathered evidence for the “prion” hypothesis, ie, the idea that diseased tau propagates and “infects” neighboring neurons in the brain. Has this been accepted in the scientific community?
MD: I think it is now fairly well accepted by the community that prion mechanisms play a role in pathogenesis. Whether it’s accepted as playing the major role is debatable. Obviously, I think that this is the main way that the disease progresses.
KF: I haven’t been directly involved with this line of research; however, our study does build on it. The prion hypothesis provides a mechanism by which the antibodies might be effective, ie, that antibodies exert their effect on the extracellular tau that has been released. Our research found that antibody binding to extracellular tau has two effects. 1) It can directly inhibit the uptake into a neighboring neuron, and 2) it reduces the amount of tau that is in the extracellular space by tagging it for clearance by microglia.
Q. So far your experiments were done in a “petri dish” using tau from humans and from mouse models of Alzheimer’s disease. What’s next?
KF: The experiments published in this paper were done in a petri dish; however, this study was a little backwards from what you might consider the normal progression. We have actually already done the in vivo study that found that these antibodies effectively reduce pathology in animals that are genetically prone to develop pathology. This work was really focused on how they work to guide development of future treatments. We are now using this knowledge to screen additional antibodies to find any that may be more effective or may work via a different mechanism.
Q. Do they target only diseased tau, or could it be a challenge getting antibodies to target diseased vs. normal tau?
KF: In the healthy brain, tau exists as a monomeric protein [ie, it binds to similar molecules to create a tightly organized tubular shape]. It is only in disease that tau self-associates and aggregates into the misshapen fibrillar form [eg, tau tangles]. Our results from this study showed that these antibodies are able to target only the aggregated tau and not the monomeric tau, even if it is purified from brain affected by AD. Furthermore, in the healthy brain, tau resides inside the cell. Most studies have indicated that antibodies are not able to enter the cell on their own, but rather only will access tau that has been released from the cell. So there is not much concern for these antibodies targeting healthy tau.
MD: This could be a challenge, especially if extracellular tau plays a key role in normal neuronal function. However, tau knockout mice appear to be quite healthy overall, as do mice that have had transient brain-specific knockdown of tau expression.
Q. Does “normal” tau serve a useful function in the brain?
KF: The complete role of tau in normal brain is not entirely clear. The most well-known function is in binding and stabilizing microtubules, which are part of a cell’s skeletal structure. There are several proteins that can compensate for tau if it is missing, so we are not very concerned with antibodies affecting healthy tau.
Q. How important is it to get rid of all the misshapen tau that’s floating around in the brain, to keep it from spreading? Is there a threshold level that the body can keep under control?
MD: We would guess that there is probably a lower threshold of tau, below which the brain can manage just fine.
KF: Because tau is a normal protein that is quite abundant in the brain, it is not a realistic goal to try to completely remove all misshapen tau. Even if we remove all of the misshapen tau, there is likely more being formed every day. Our goal is to try to reduce the amount of misshapen tau so that we can slow the progression of the disease. Right now, the best treatments we have for AD reduce the loss of cognition for up to six months. Treatment that delays the progression of disease for even a couple of years would be a welcome respite for those who are affected.
Q. What’s the brain environment like when tau starts spreading? Do the antibodies you’ve developed, in a sense, trigger the body’s innate immune function?
KF: The aged brain tends to be in a more active inflammatory state. The exact reason for this, and whether this is helpful or harmful during AD, is still unclear. One school of thought posits that the immune cells in your brain, microglia, can become frustrated by the chronic inflammation and not very efficient at recognizing factors that are causing inflammation, thus perpetuating the cycle. Because tau is a protein that is found in healthy brain, the body’s immune system doesn’t effectively recognize it as foreign. The antibodies act as a signal to the microglia that this protein is undesirable. So yes, the antibodies are basically tagging the misfolded protein for your immune system to recognize it and remove it.
Q. Obviously, you plan to take this initial success story further, towards development of an antibody-based vaccine for humans. How long might such a vaccine offer protection? Weeks? Months? Years?
MD: I would envision that a passive vaccine would be given roughly every 1 to 3 months by intravenous or intramuscular administration. Right now there is relatively limited enthusiasm for an active vaccine, based on the side effects that occurred following active immunization against amyloid beta.
Q. The brain fiercely protects itself by keeping out foreign agents. How would you get a vaccine into the mouse or human brain?
MD: Work that was recently published from the Holtzman lab suggests that peripheral administration of an anti-tau antibody has a beneficial effect. Either very small amounts of antibody have a good effect in the brain, or peripheral antibody is trapping brain-derived tau.
Q. Aβ plaques can accumulate in the brain over decades without causing Alzheimer’s symptoms. However, when tau tangles get on the scene, things seem to go downhill rapidly. When in the disease process would a tau vaccine be most effective?
MD: I would envision that a tau vaccine would be most effective before symptoms start. This could be after the accumulation of Aβ peptide. However, given our understanding of the pathogenic mechanism, I think it is likely that a vaccine given even after the start of symptoms would be beneficial, as it could potentially prevent further neuronal loss, and recovery of damaged neurons that are not yet dead.
KF: A huge barrier to progress for the development of treatment for AD has been relatively late diagnosis of the disease. It is now thought that by the time patients are symptomatic, it may be too late for intervention. In our animal models, we have had our greatest success in starting treatment at the same time that tau pathology is starting to develop. Most likely, antibody treatments will be most effective at halting the progression of the pathology rather than reversing pathology that has already developed. I think research in early diagnosis will be vital to the success of antibody therapy, and probably many other therapies as well.
Q. Is there any hope a tau vaccine might be available in 15-20 years, as the first of the Baby Boomers move through their 80s and become prime candidates for late-onset Alzheimer’s?
MD: One of the antibodies that Kristin studied has been licensed, and is now entering early clinical trials. In this case, the turnaround time between characterization of the antibody in vitro and in mice to introduction into patients was less than five years.