An innovative imaging technique has revealed that the plaques that develop throughout the brains of Alzheimer's patients can form overnight, and they are likely a cause rather than a symptom of the disease.
Plaques, a defining hallmark of Alzheimer's disease, are brain lesions that result from the abnormal accumulation of a protein called amyloid-beta. Since the symptoms of the disease progress over the course of decades, plaques were generally thought to appear and accumulate slowly.
"The notion was that since the disease plays out over a long period of time, individual lesions in the disease process would also have that same tempo," says Bradley Hyman, director of the Alzheimer's unit at Massachusetts General Hospital's MassGeneral Institute for Neurodegenerative Disease.
Hyman's team harnessed a fledgling imaging technique called multiphoton confocal microscopy to peer into the brains of living mice. The technique generates images using rapidly pulsed lasers that penetrate deep into living tissue without damaging it. By cutting out tiny sections of skull and replacing them with glass, the researchers created windows into the brains of mice that were genetically engineered to develop amyloid plaques. They could then repeatedly observe the same area of brain, and thus follow plaque formation over time.
"This gives us an opportunity to apply a time stamp to the events that are occurring," says Hyman. "So rather than simply having an individual snapshot of a pathophysiologic event, we can watch the process evolve."
While groups have applied multiphoton confocal microscopy to living brains before, Hyman's group is the first to apply the technique to the study of a neurodegenerative disorder. "It really pushes the technology forwards," says Steven Finkbeiner, associate director of the Gladstone Institute of Neurological Disease at the University of California, San Francisco, who was not involved with the study.
Besides revealing the surprisingly fast pace of plaque formation, the study addresses a long-standing debate over the role of amyloid plaques in the development of Alzheimer's disease.
A long-established hypothesis posits that amyloid plaques themselves bring about damage to neural tissue, causing the disease's symptoms--most notably behavioral changes, memory loss, and dementia. But some scientists counter that plaques are not correlated strongly enough with the disease to be a convincing culprit for its symptoms. Rather than causing the symptoms of Alzheimer's, plaques could themselves be symptoms--stemming from some other, yet unknown mechanism.
"There's always been a lot of debate," says Juan Troncoso, codirector of the Alzheimer's Disease Research Center at Johns Hopkins School of Medicine, who was not involved with the study. "What happens first, and what's responsible for what? Is the damage to the nerve cells first, and then the plaque, or vice versa?"
Because the new imaging technique followed plaque formation in detail over many days, it could address this chicken-and-egg conundrum as previous approaches could not. "When you only have single snapshots of the process, it's hard to be sure how to interpret causation," says Hyman.
Hyman's team found that plaque formation was indeed the first step in the process, with amyloid-beta protein depositing into an aggregate that appeared quickly and continued to grow. Next, immune cells called microglia were activated and flocked to the area. In the ensuing days, a halo of damage began to appear around the plaque. Nearby neurons became distended and twisted into abnormal, corkscrew-like shapes, likely hampering their ability to transport critical cell components and communicate with one another.
"The bottom line," says Troncoso, "is that this study establishes that at least in the mouse, the plaque is the first step." This kind of investigation would not be possible in humans for ethical reasons, and there's no guarantee that the mechanism observed in mice is the same one that takes place in the brains of human Alzheimer's patients. But Troncoso says that the results are relevant nonetheless. "These animal models are our best available tool to try to understand these types of processes," he says.
Finkbeiner agrees that Hyman's results implicate amyloid plaques as the instigators of the neural damage that surrounds them. "I think this study clearly establishes that the dystrophy that you see in association with plaques does occur after the plaque forms," he says. But he contends that there is still no powerful evidence that such damage is to blame for the primary symptoms of Alzheimer's.
"I don't doubt for a minute that dystrophy does have deleterious consequences for the neurons involved," says Finkbeiner. "But it probably doesn't explain the majority of symptoms that people get with Alzheimer's disease."
Hyman maintains that the local damage associated with plaques could very well underlie the systemic disruption in neural function that characterizes the disease. "Ultimately, the types of changes that we see, I think, lead to a breakdown in the connections of the brain," he says.
If that is the case, preventing amyloid buildup is likely to be a key strategy in treating Alzheimer's. According to Troncoso, since the study "strongly suggests that amyloid is a very early event in the development of Alzheimer's disease, the corollary would be that it becomes the therapeutic target of choice."
Hyman plans to probe the plaque formation process in more detail, investigating how the amyloid-beta protein develops into a full-blown plaque, and how it brings about the observed changes in neighboring neurons.
Illustration: Because Alzheimer's disease develops over the course of decades, many scientists assumed that its hallmark brain lesions, called amyloid plaques, were slow to appear. A new imaging technique called multiphoton confocal microscopy reveals that on the contrary, plaques can form in a single day. This image (pictured) of a mouse's cortex shows a mature plaque (large blue splotch) with a brand-new "microplaque" (small blue dot within the white square) developing beside it. Reimaging the same brain area over several subsequent days showed the plaque growing. --Nature Publishing Group.
Massachusetts General Hospital News Release (02/06/08)
Technology Review (02/08/08)
Abstract (Nature 451, 720-724 (02/07/08))