In Search of the Origins of Neurodegenerative Disease


by Jim Schnabel

January 26, 2011

All the major neurodegenerative diseases feature deposits of sticky, insoluble protein aggregates in the brain, the best-known example being the plaques of amyloid-beta (A-beta) protein and tangles of tau protein in Alzheimer’s disease. But researchers suspect that these large aggregates are not the main problem, and that smaller, still-soluble protein clusters, known as “oligomers,” are the true, toxic drivers of disease. There are even hints that the larger aggregates might help the brain by capturing and containing the smaller and more dangerous oligomers. (See story, “More Evidence that Clusters of Proteins May Drive Disease”).

But how does this clustering process that leads to oligomers and larger aggregates get out of control in the first place? Is it that cluster-prone proteins such as A-beta are overproduced? Or is it that our natural cellular defenses against these protein formations are impaired, perhaps with aging?

“These are questions that we’re keenly interested in answering,” says Randall Bateman, a neurologist at Washington University of St. Louis, and senior author of a study that strongly implicates impaired defenses in the genesis of common forms of Alzheimer’s.

Impaired clearance in Alzheimer’s

The study by Bateman and colleagues, first-authored by staff scientist Kwasi Mawuenyega, appeared on Dec. 9, 2011, on the journal Science’s website Science Express. Using a radioactive labelling technique, the researchers tracked the synthesis and the removal, or “clearance,” of A-beta in the central nervous systems of twelve people with the common, late-onset form of Alzheimer’s disease, and twelve age-matched and cognitively normal controls.

The rate at which new A-beta proteins were being synthesized was the same in both groups. But the rate of A-beta clearance among the Alzheimer’s patients was about 30 percent lower than it was in the cognitively normal subjects. The researchers estimated that this 30 percent imbalance between production and clearance would have taken about a decade to load the brain with typical Alzheimer’s-associated levels of A-beta, a figure broadly consistent with what is known about the disease’s gradual development.

Why was A-beta clearance reduced in these patients? “It’s not a simple question to answer in humans,” Bateman says, because there is more than one clearance mechanism that could be relevant.

One set of mechanisms involves cellular garbage-disposal systems that capture unwanted aggregates of all sorts and digest them into harmless pieces. Other mechanisms transport A-beta away from brain tissue into the bloodstream and cerebrospinal fluid, where A-beta clusters may do less harm and/or can be cleared more easily. “As soon as A-beta hits the bloodstream, for example, it’s cleared within minutes to a much lower concentration than exists in the brain,” says Bateman.

Studies in animal models have hinted at the importance of all these mechanisms, he adds, but more conclusive tests in humans, with regard to Alzheimer’s and other neurodegenerative diseases, still lie in the future.

The advantages of youth

“I certainly believe that diminished clearance has an important role in these diseases,” says biochemist and neurodegenerative disease researcher Jeffery Kelly of the Scripps Research Institute, who was not involved in the Washington University research. So far, though, he adds, the best-studied risk factors lie on the production side, in rarer, familial forms of these diseases:  “There’s much more evidence for gene duplication and triplication [leading to protein overproduction], and mutations that make proteins more likely to form oligomers,” he says.

Gene mutations that cause familial Alzheimer’s, for example, seem to do so either by increasing production of A-beta generally or by increasing production of a longer, more cluster-prone form of the protein. Parkinson’s disease also has been linked to rare genetic mutations—and even relatively common gene variations—that increase production of the cluster-prone alpha synuclein protein. Huntington’s disease is always caused by genetic mutations that produce longer, more cluster-prone forms of the huntingtin protein. 

But are these production-driven forms of neurodegenerative disease the exceptions that prove the rule? People who have these production-side defects somehow almost always live symptom-free well into adulthood. In the case of Alzheimer’s, notes neurologist Peter St. George-Hyslop at the University of Toronto, people with genetically overproduced A-beta typically live normally “for 40 years before they actually come down with the disease, so there definitely is a change in something other than just the production of A-beta.”

That fatal change may be an aging-related decline among neuronal defense mechanisms, and as Hyslop says, such a decline may involve a reduction in the efficiency of aggregate clearance mechanisms, or simply a decline in more general mechanisms that enable neurons to withstand the stresses of disease—or both.

Further evidence for the importance of clearance mechanisms

There are also more-direct hints from genetic studies about the importance of clearance mechanisms. Several of the known familial forms of Parkinson’s disease, for example, involve genes whose normal protein products are somehow involved in major aggregate-disposal systems within cells. One of these genes, parkin, causes an early-onset form of Parkinson’s when mutated; it is suspected that these parkin mutations cause disease by impairing the ubiquitin-proteasome system, a waste-disposal route that normally helps clear unwanted aggregates. Studies using genetically engineered mouse models suggest that some of these neurodegenerative disease-driving aggregates may directly weaken cellular waste-clearance systems, blocking their smooth operation and leading to a general buildup of wastes.

Genetic studies of people with common, late-onset Alzheimer’s disease also have found that the presence of the E4 variant of the apolipoprotein-E gene is a major risk factor. Most people born with two copies of the apo-E4 variant will develop Alzheimer’s by their late 60s. A study in 2008 by researchers including Bateman’s colleagues at the University of Washington linked apolipoprotein-E to the clearance of soluble forms of A-beta, and found that the E4 variant seems less efficient at this task than the other common forms.

Kelly points out that “the [apo-E4] mechanism is still not clear.” But so far there is more than enough evidence to persuade some labs that aggregate clearance mechanisms—or what is more broadly referred to as the “proteostasis network”—could be a useful target for drugs. Kelly says his lab’s “main role right now is to understand how to adapt the proteostasis network to delay if not prevent the onset of these diseases, and certainly one of the things we’re working hard on is to upregulate the clearance mechanisms.”

Hyslop also finds this a sensible strategy. “If you could rev up the [neuronal defense-related] genes that are downregulated and causing the disease to become apparent at a certain age, you could do away with or at least delay the disease, which would be fantastic.”