Everyone has a brain that has the tools to develop Alzheimer’s disease. Why therefore do some people develop Alzheimer’s disease (AD) while others do not? An estimated five million Americans have AD – a number projected to triple by 2050– the vast majority of people do not and will not develop the devastating neurological condition. What is the difference between those whole develop AD and those who do not?
Subhojit Roy, associate professor in the Departments of Pathology and Neurosciences at the University of California, San Diego School of Medicine, asked this exact question. In a paper published in the journal Neuron, Roy and colleagues offer an explanation for this question. As it turns out, in most people there is a critical separation between a protein and an enzyme that, when combined, trigger the progressive cell degeneration and death characteristic of AD.
“It’s like physically separating gunpowder and match so that the inevitable explosion is avoided,” says principal investigator Roy, a cell biologist and neuropathologist in the Shiley-Marcos Alzheimer’s Disease Research Center at UC San Diego. “Knowing how the gunpowder and match are separated may give us new insights into possibly stopping the disease.”
Neurologists measure the severity of AD by the loss of functioning neurons. In terms of pathology, there are two tell-tale signs of AD: a) clumps of a protein called beta-amyloid “plaques” that accumulate outside neurons and, b) threads or “tangles” of ‘tau” protein found inside neurons. Most neuroscientists believe AD is caused by the accumulation of aggregates of beta-amyloid protein, which triggers a sequence of events that leads to impaired cell function and death. This so-called “amyloid cascade hypothesis” puts beta-amyloid protein at the center of AD pathology.
Creating beta-amyloid requires the convergence of a protein called amyloid precursor protein (APP) and an enzyme that cleaves APP into smaller toxic fragments called beta-secretase or BACE.
“Both of these proteins are highly expressed in the brain,” says Roy, “and if they were allowed to combine continuously, we would all have AD.”
It sounds inexorable, but it doesn’t always happen. Using cultured hippocampal neurons and tissue from human and mouse brains, Roy and Utpal Das, a postdoctoral fellow in Roy’s lab who was the first author of this paper, and other colleagues, discovered that healthy brain cells largely segregate APP and BACE-1 into distinct compartments as soon as they are manufactured, which ensures that these two proteins do not have much contact with each other.
“Nature seems to have come up with an interesting trick to separate co-conspirators,” says Roy.
What then brings APP and BACE together? Roy and his team found that those conditions that promote greater production of beta-amyloid protein also increase the convergence of APP and BACE. Specifically, an increase in neuronal electrical activity, which is known to increase the production of beta-amyloid, also increased the convergence of APP and BACE. Post-mortem examinations of AD patients have shown that the cellular locations of APP and BACE overlap, which lends credence to the pathophysiological significance of this phenomenon in human disease.
Das says that their findings are fundamentally important because they elucidate some of the earliest molecular events triggering AD and show how a healthy brain naturally avoids them. In clinical terms, they point to a possible new avenue for ultimately treating or even preventing the disease.
“An exciting aspect is that we can perhaps screen for molecules that can physically keep APP and BACE-1 apart,” says Das. “It’s a somewhat unconventional approach.”