The Missing Link in Alzheimer's Research

One hundred years ago, when Alois Alzheimer, a German psychiatrist and neuropathologist, first described Alzheimer’s disease, it was quite rare. Alzheimer’s is a disease of aging. At a time when the average human lifespan was less than 50 years, few people lived long enough to be at risk for the disease.

Today this is no longer the case. Advances in medical care have dramatically extended our lifespan. Approximately 4.5 million Americans currently have the disease, including half the population over 85. With the graying of the baby boomers, the number of people with Alzheimer’s is expected to reach as high as 16 million by 2050. To date, successful treatment has been elusive, but work being done by George Bloom, a professor of biology and cell biology, is shedding light on the underlying causes of this disease and pointing the way to therapies that could halt its progression.

The hallmarks of Alzheimer’s disease are the fibrous plaques made from a protein fragment known as beta-amyloid that pile up outside the neurons in the brain and the tangles of a protein called tau that accumulate inside them. One assumption that researchers have made is that plaques cause the death of brain cells. Bloom’s work suggests that both the plaques and the tangles might be side effects of a more insidious process that destroys the axons, the long extensions that connect neurons to each other through specialized structures called synapses. These synapses are essential for cognition and memory.

With Michelle King, a research assistant professor of biology, Bloom has found that when nerve cells are dosed with even a small amount of a rogue, preplaque form of beta-amyloid, it interacts to disastrous effect with naturally occurring tau within the nerve cell.

Tau is a protein produced almost exclusively by neurons that plays a critical role in maintaining the integrity of the axon’s micro-tubules. Microtubules are fibers that serve as intra-axonal highways along which synapse replacement parts travel from their sites of production in the neuronal cell body to the tips of the axons. When neurons are exposed to preplaque beta-amyloid, their microtubules fall apart. Then the synapses shut down, and the cell dies. Tau is necessary for these events to happen. Bloom and King found that cells without tau show no response in the presence of preplaque beta-amyloid.

It would be difficult to overestimate the importance of this research. Bloom and King have found the first evidence for the long-elusive missing link between beta-amyloid and tau. “We think we’ve found one of the seminal cell biological events in the development of Alzheimer’s disease,” Bloom says. “If we can figure out all of the steps in the process and understand each player at every step, every new player will represent a potential new drug target for Alzheimer’s therapy.”