Exciting news travels from Washington University of St. Louis (WUSL), where two BrightFocus-funded Alzheimer’s researchers recently had their results published in major scientific journals. Both projects were directly funded by BrightFocus.
One paper represents an innovative strategy directed towards apolipoprotein E (apoE)—a factor associated with late-onset Alzheimer’s disease. Years ago, scientists pinpointed a variation of the apoE gene as the most important genetic risk factor for late-onset Alzheimer’s disease, but “only recently, with the help of BrightFocus’ donor support, have we begun to understand what it is doing,” commented Guy Eakin, BrightFocus vice president for Scientific Affairs.
The other paper represents a return to the “prion hypothesis”—the idea that Alzheimer’s is driven by the spread of protein aggregates in the brain. Nobel Laureate Stanley Prusiner, MD, a former BrightFocus grantee, coined the term “prion” and was one of the original proponents of this idea. Decades of research supported by BrightFocus and others led to his winning the Nobel Prize in 1997.
Both reports are getting attention in the world of science and taking us further down the road towards understanding and ultimately curing the 21st Century Alzheimer’s pandemic.
Fighting Apolipoprotein E with Monoclonal Antibody
BrightFocus grantee Fan Liao, PhD, and colleagues have reported success in reducing beta amyloid plaques and Alzheimer’s symptoms in mice after using immunotherapy to modulate apolipoprotein E (apoE) levels. Their work was published in the Journal of Neuroscience on May 21 (Liao et al, 2014). Liao works in the lab of David M. Holtzman, PhD, senior author, whose earlier BrightFocus grant led to the discovery that immunotherapy slowed beta amyloid buildup and prevented new plaque formation in mice.
In these latest experiments, they treated mice that had plaques with an anti-apoE monoclonal antibody and found that, over time, blocking apoE in this way helped to prevent new beta amyloid plaque formation, inhibited existing plaque growth, and improved brain function in treated mice. In the most impressive display of science, these researchers directly applied the monoclonal antibody to existing plaques on the brain surfaces of live mice and observed that, over a period of weeks, some of the existing plaques shrunk or disappeared altogether.
In a published interview, Holtzman said it’s unclear exactly how the plaque formations were eliminated in the mouse brain—i.e., whether by binding to apoE or stimulating other brain cells “to gobble up plaques.” This will be investigated further. Either way, these promising results, captured on photon microscopy, signal hope that someday there may be a way to rid the human brain of such plaques.
Why Are These Results Important?
Late-onset Alzheimer’s is by far the most common form of the disease, affecting an estimated one in 9 individuals aged 65 years and older (Herbert et al, Neurology, 2013). Given existing clues, and a chance to intervene where the disease hits hardest, numerous researchers have focused on the apoE gene. BrightFocus has funded dozens of these projects.
However, apoE has remained an elusive target; for example, there were conflicting reports about whether lowering or raising apoE levels would do the most good to prevent beta amyloid buildup. As a result, apoE was never really spotlighted as a potential therapeutic target—until now.
The results by Liao et al, as well as those appearing in the same journal issue by a team who manipulated apoE in a completely different fashion, have thrust apoE forward into the limelight. It’s now on the short list of potential weapons against Alzheimer’s. Alzheimer Forum, a science networking group, paid tribute to both discoveries in a commentary entitled, “Has ApoE’s Time Come as a Therapeutic Target?”
“Although it’s still early, and in a mouse study, this new paper is a pretty big deal,” Eakin commented on behalf of BrightFocus. “It’s also a promising example of how our donor support for innovative and creative research advances the field.”
A Return to Prions
The second publication hails from the lab of 2010-13 BrightFocus grantee Marc Diamond, MD, at WUSL. They have demonstrated that the tau protein, another type of amyloid protein associated with Alzheimer’s disease, may be corrupted by strains of “miscoded” proteins that act very similarly to prions. The study, led by co-first authors David Sanders and Sarah Kaufman, was published online in Neuron on May 22, with Diamond as senior author.
In Alzheimer’s disease, tau collects in fibrous deposits known as “tau tangles” that appear to damage and destroy neighboring brain cells. The growth of lethal tau formations, known as “tauopathy,” has been associated with 25 different neurodegenerative disorders.
Prions are composed of normal proteins that have folded into an abnormal shape.
While early Alzheimer’s research focused on prions as a possible cause of disease, their possible role became overshadowed by the discovery of beta amyloid plaques. However, in 2009, Diamond’s group found that tau misfolds into several different shapes in a test tube, and that discovery led him and others to suspect that “prions” may be involved in tauopathy and could be a root cause of the brain’s pathologic changes with Alzheimer’s.
Evidence Corroborated in Different Experiments
On a WUSL news site, Diamond described the team’s latest work. “When we infected a cell with one of these misshapen copies of tau and allowed the cell to reproduce, the daughter cells contained copies of tau misfolded in the same fashion as the parent cell,” he said. “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. This proves that each of these differently shaped copies of the tau protein can form stable prion strains, like a virus or a bacteria that can be passed on indefinitely.”
They next used the tau prions made in cells to infect mouse brains, showing that differently shaped strains caused different levels of brain damage. He isolated the prions from the mice, grew them in cell culture, and then infected other mice. Throughout these transfers, each particular prion strain continued to be misfolded in the same shape and to cause damage in the same fashion.
Finally, these results were corroborated in human experiments. Researchers examined clumps of tau from the brains of 28 patients after they died. Each of the patients was known to have one of five forms of tauopathy, identifiable by a unique tau prion strain or combination of strains.
In the human brain autopsies, “we isolated the same tau prion strain from nearly every patient with Alzheimer’s disease we examined,” Diamond said.
Now the team is working on a way to isolate tau prions, noninvasively, for diagnostic purposes in humans. One option for stopping them might be monoclonal antibodies—or duping the body’s own immune system into attacking and removing the prions (see note on how monoclonal antibodies work, below). Others include blocking tau prion movement between cells and stopping cells from making new copies of the prion proteins.
Where Next with the Prion Hypothesis?
Visualizing and understanding how cells in the brain metamorphose from “normal” to “Alzheimer’s disease” is a fascinating field. It has captured some of the most intuitive and engaging minds in science, powered by state-of-the-art imaging techniques. Only by understanding how Alzheimer’s starts will we be able to stop it most effectively.
The prion hypothesis, put into perspective, is one of several existing theories about how molecules move between cells, and how that movement might propagate Alzheimer’s disease. The Diamond lab has provided some of the most convincing evidence to date, and their ideas are presented clearly.
Much more research is needed, however, to determine whether Alzheimer’s disease mimics other prion-caused neurodegenerative disorders, as Diamond et al suggest. Stay tuned: BrightFocus has multiple grants addressing the topic from different angles.
Q. What is the connection between apoE and Alzheimer’s disease?
A. For years scientists have had their eye on apolipoprotein E (apoE), a small protein which combines with fats in the body to form molecules (“lipoproteins”) that carry cholesterol and other fats though the bloodstream. ApoE also influences the brain’s ability to clear beta amyloid and keep it from congregating in plaques.
There are at least three different versions (alleles) of the apoE gene in humans, and the apoE4 allele is known to be a bad player when it comes to both cardiovascular risk and Alzheimer’s disease. People carrying the apoE4 allele are at greatest genetic risk for late-onset Alzheimer’s disease, and their onset of memory loss and other symptoms appears to be more rapid than for other groups. They also have been found to have a greater build-up of amyloid plaques in their brain tissue.
While having the apoE4 allele leads to an increased risk of Alzheimer disease, not all people with Alzheimer disease have the apoE4 allele, and not all people who have this allele will develop the disease.
Q. Is a monoclonal antibody a drug, and how does it work?
A. Monoclonal antibodies are relatively new to medicine, having emerged on the clinical scene within recent decades. They are not “drugs,” per se, but belong to a new FDA category of live, genetically-engineered treatment approaches known as “biologic agents.” All monoclonal antibodies are assigned a generic name ending in “mab.”
Monoclonal antibodies are produced in the lab using cell replication techniques—in this case to produce identical immune cells that are all clones of a unique parent cell. As such, they can accurately and predictably detect and bind to specific cells or molecular formations in the body, and thus can be used to block or instigate the body’s own biochemical responses.
Q. What are prions and what makes them spread?
A. Prions are normal proteins that have folded into an abnormal shape. They aren’t alive, but their effects can be similar to infectious microbes such as bacteria or viruses. That’s because they have a unique structure that can influence surrounding molecules, causing them to take on different shape and molecular structure. For example, when a prion interacts with identical but normally folded proteins, it can cause these proteins to become prions, which are small aggregates, or clumps, that then spread from cell to cell.
Q. If prions cause Alzheimer’s disease, does that mean it’s contagious?
A. Not necessarily. Transmissibility from one cell to another in the brain does not equate to the disease’s ability to replicate outside the brain environment.
Some experts have hypothesized that Alzheimer’s and other amyloid-linked diseases may be “self-propagated,” possibly beginning with seed cells that become molecularly unstable and susceptible to prion-like infection from age or environment-related changes (refer to Alzheimer’s Disease: Return of the Prion Hypothesis). Others, including Diamond, agree that spontaneous transmission between people is unlikely, but caution that under the right circumstances—tissue transplantation, for example—pathogenic proteins such as tau could conceivably be passed among individuals.
Now and in the future, a lot of molecular firepower will be aimed at answering these questions. In the meantime, even though no one’s been known to “catch” Alzheimer’s disease from another individual, stories about it being “infectious” are apt to be sensationalized in the popular media. Take them with a grain of salt.
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