FACULTY SYMPOSIUM

New Hopes for Treating Brain Disease

On a recent trip to Rome, while taking in the grandeur of the Sistine Chapel, Joseph Martin and his wife, Rachel, saw a woman point up at Michelangelo’s Creation of Adam and make a startling claim. She said that the painting—which famously depicts God reaching out from a billowing cloak full of angels—was actually a thinly disguised rendering of the human brain.

“I thought this was nonsense,” said Martin, the Edward R. and Anne G. Lefler professor of neurobiology and former dean of the Faculty of Medicine. He spoke on June 5 at the HMS Faculty Symposium, “Neurodegenerative Disease: New Developments and New Hopes.” Back in Boston, Martin came across a 1994 paper arguing that Michelangelo, who had dissected numerous cadavers, intended to show God bestowing intellect on Adam—not life, as many assumed—and used the image of the brain to reinforce his message.

“You’ll notice, even more important, that Michelangelo painted a synapse,” said Martin, zooming in on God’s and Adam’s nearly touching fingers.

Martin’s comments, which came at the beginning of the symposium, were apt as well as colorful. Synaptic failure is at the core of most neurodegenerative diseases, from Alzheimer’s and Parkinson’s to amyotrophic lateral sclerosis (ALS). But they were fitting for another reason. These diseases hold iconic images of their own—the plaques and tangles of Alzheimer’s disease, the Lewy bodies of Parkinson’s. Traditionally thought to be agents of disease, these dense clots of protein have come in for reinterpretation. Some believe they may actually rescue the brain from the real culprits—smaller, synapse-disrupting protein fragments.

The three-hour symposium was devoted to describing efforts to capture and thwart these rogue peptides and to restore synaptic function to diseased brains.

“I have an interesting story to tell,” said Dennis Selkoe, the Vincent and Stella Coates professor of neurologic disease in the Department of Neurology at HMS and Brigham and Women’s Hospital. For years, he and colleagues have been arguing that Alzheimer’s is the consequence of the overproduction of amyloid beta42 (Abeta42), a component of plaques, by a set of enzymes called the secretases.

To test their hypothesis, he and colleagues, including Ganesh Shankar, exposed slices of rat hippocampus, the brain region involved in memory formation, to soluble Abeta taken from the brains of patients with Alzheimer’s and other memory-impairing disease. The hippocampal synapses did not function normally. The researchers repeated the experiment, this time exposing the neurons to amyloid plaques from which all the Abeta was removed. “There was no perturbation of the signal,” Selkoe said.

Though Abeta is found in plaques, some think its presence there is a consequence of the brain’s effort to sequester the nimble Abeta oligomers. “We think the plaques are protective, but it’s the soluble oligomers that go in and interrupt synaptic function,” Selkoe said. One strategy to stop the rogue peptides would be to target the secretases that make Abeta in the first place. Another would be to get the immune system of patients to attack Abeta peptides. This vaccine approach has yielded promising results in clinical trials, in some cases helping to stave off mental decline in subjects.

Graham Ramsay

“In all of these neurodegenerative diseases, synapses are at the core,” said Dennis Selkoe. He appears with (from left) Reisa Sperling and Merit Cudkowicz.

An even more effective measure would be to monitor the appearance and spread of Abeta in the brain. “We need to ultimately image the small bits of amyloid, the dimers and trimers,” said Reisa Sperling, HMS associate professor of neurology at BWH. “We’re not there yet.”

In contrast to Alzheimer’s disease, with its slow spread, ALS cuts a swift and deadly course, destroying motor neurons in the brain and spinal cord within two to five years, though some patients can live much longer, said Merit Cudkowicz, HMS associate professor of neurology at Massachusetts General Hospital. Unlike Alzheimer’s with its telltale plaques and tangles, there are no distinguishing hallmarks of disease. Several years ago, Robert Brown, HMS associate professor of medicine at MGH, and colleagues identified a mutant form of the protein, SOD1, in families affected by the disease. Researchers have since identified several more loci in familial forms, which has led to the development of a wide array of animal models.

Researchers recently found that a well-known antibiotic, ceftriaxone, delayed loss of muscle strength and body weight in a mouse model of ALS. Cudkowicz is part of a consortium involving the ALS Association and the National Institute of Neurological Disorders and Stroke (NINDS) that has been testing the drug in humans. “We are currently expanding the 60-person study to 600,” she said.

Though there are not yet effective treatments, patients are living longer thanks to the use—early in the course of disease—of assistive devices such as G-tubes, noninvasive ventilators, and exercise programs. “One of the largest advances has been in improved care,” Cudkowicz said. “It has shifted survival dramatically.”

—Misia Landau

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