G. William Rebeck: Researching Alzheimer’s - What is Normal?

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In order to understand disease, you need to know what “normal” is. G. William Rebeck, PhD, has been trying to apply this principle to Alzheimer’s disease: What is the natural function of the protein—amyloid precursor protein (APP)— that is blamed for the disease, a portion of which can clump together into plaque and clog the brains of patients?

Despite decades of research on toxic forms of the APP molecule, no one has been able to describe what role APP plays in normal brain function.

“I started working on Alzheimer’s disease in 1991,” says Rebeck, who received his doctorate from Harvard University that same year. “And my boss, who led a team that had just cloned APP, kept saying that we won’t understand Alzheimer’s disease until we find out its normal function.”

Rebeck’s research now points to an answer – one that is elegant in its simplicity.

What has long been known is that mutations in the gene that produces APP causes an inherited form of Alzheimer’s disease, and that APP can be cut by enzymes into shorter pieces of protein known as amyloid beta (A-beta). Certain forms of A-beta stick together to form the plaque found in the disease.

“In the last 20 years we have made tremendous progress in understanding how APP can become toxic. We understand how the protein is cut to make A-beta and we are even testing drugs to counteract this slicing,” Rebeck says. “But I think the flip side is equally interesting: Why is APP even in the brain?”

To answer that question, Rebeck and his GUMC collaborator, Hyang-Sook Hoe, PhD, have performed experiments in which they over-expressed APP in neurons in laboratory culture or reduced their levels. They then measured changes in the normal functioning of the neurons.

The results, included in studies that are newly published and others in press, suggest that APP actually acts like a structural bridge to stabilize the synaptic space between two neurons. Neurons, aligned in circuits, send chemical signals to one another to control systems in the body. The presynaptic neuron releases neurotransmitters to the postsynaptic neuron, and APP’s job is to promote the structure of these synapses, Rebeck says.

“APP is important to keep synapses stable and to have the receptors in the right place and working,” he says.

This also explains, in theory, how APP could contribute to loss of neurons in disease, Rebeck says.

The brain is very plastic, and is constantly reorganizing itself, he says. “We learn new things all the time but we only have so much hardware, so sometimes the connection between neurons needs to be broken. Do we need to remember where we parked a car two years ago?”

To sever that connection, neurons get rid of their synapse by cutting APP apart, producing A-beta, which is toxic to the synapse.

All that is fine until the process goes awry – and that would most likely happen in an older brain. “The biggest risk factor for Alzheimer’s disease is age and the earliest pathology is the loss of synapses and a halt in communication between neurons.

“I see the process occurring as a positive feedback loop,” he says. “A little bit of A-beta from a dying neuron damages synapses in near-by neurons, leading them to cut their APP and produce more A-beta. In this downward spiral, neurons continue dying and the A-beta accumulates as plaque.”

Rebeck says there is much to be proven yet before the Alzheimer’s disease research community determines whether this idea is right. But he adds that it is about time an answer is provided.

“Understanding APP will help us anticipate possible side effects of treatments that alter APP metabolism, and may originate new ideas about how A-beta production is normally regulated – and how we can alter it to treat or prevent Alzheimer’s disease,” he says.

By Renee Twombly, GUMC Communications