Imaging technique sheds light on Alzheimer?s development

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Plaques that develop throughout the brains of Alzheimer's patients can form overnight, and are more likely a cause, not a symptom, of the disease, according to a study published in the Feb. 8 issue of Nature.

Plaques are brain lesions that result from the abnormal accumulation of the protein amyloid-beta. Since the symptoms of Alzheimer’s progress over the course of decades, plaques were thought to appear and accumulate slowly, according to Bradley Hyman, director of the Alzheimer's unit at Massachusetts General Hospital's Institute for Neurodegenerative Disease.

In his research, Hyman found evidence that suggests that plaques can develop in a single day.

Hyman's team harnessed multiphoton confocal microscopy to peer into the brains of living mice using rapidly pulsed lasers that penetrate deep into living tissue without damaging it.

Researchers created windows into the brains of mice that were genetically engineered to develop amyloid plaques by cutting out tiny sections of skull and replacing them with glass. They could then repeatedly observe the same area of brain, and thus follow plaque formation over time, said Hyman.

According to 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, the study addresses a long-standing debate over the role of amyloid plaques in the development of Alzheimer's disease.

One hypothesis suggests that amyloid plaques themselves bring about damage to neural tissue, causing the disease's symptoms--most notably behavioral changes, memory loss, and dementia while another counters 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, Hyman said.

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.

Finkbeiner said 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 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.

Hyman said he 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.