Now, a collaboration between researchers at the Salk Institute for Biological Studies and the Scripps Research Institute shows that aging is what's critical. Harmful beta amyloid aggregates accumulate when aging impedes two molecular clean-up crews from getting rid of these toxic species.
This finding opens the door for development of drugs preventing build-up of toxic protein aggregates in the brain. The study appears in the Aug. 10 issue of Science Express, the advanced online edition of the journal Science.
"Aging is the most important risk factor for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease," says senior author Andrew Dillin, Ph.D., an assistant professor in the Salk Molecular and Cell Biology Laboratory. "Our study revealed that the age onset of these diseases is not simply a matter of time but that the aging process plays an active role in controlling the onset of toxicity," he explains.
Beta amyloid production occurs in all brains, but healthy cells clear away excess amounts. Brains of people with Alzheimer's disease, on the other hand, are unable to control beta amyloid accumulation. For years, scientists have scrambled to find out why.
To answer this vexing question, Dillin analyzed protein aggregation in the roundworm, a streamlined organism that, like mammals, uses the insulin/IGF-1 pathway to control lifespan but can be rapidly manipulated genetically. Dillin used roundworms that produce human beta amyloid peptide in body wall muscles. As the worms aged, the protein formed toxic aggregates causing paralysis.
Then researchers experimentally decelerated aging in engineered worms by lowering activity of the insulin/IGF-1 pathway and asked whether it was simply the passage of time--not aging per se--that favored protein aggregation. It wasn't: chronologically "old" worms crawled around happily, while counterparts whose insulin/IGF-1 pathway was normal could only helplessly wriggle their heads.
However, close inspection of the data revealed a surprise: "Worms with reduced insulin signaling seemed perfectly fine although they had high molecular weight aggregates, while worms with an accelerated aging program were extremely sensitive to the toxic effects of beta amyloid but we couldn't detect any large fibrils," explains postdoctoral researcher and co-lead author Ehud Cohen, Ph.D.
Intrigued, Dillin turned to an expert on beta amyloid biochemistry, Jeffery Kelly, Ph.D., a professor of chemistry at Scripps and a member of its Skaggs Institute of Chemical Biology.
Together they found that cells use an unexpected two-pronged strategy to rid themselves of harmful aggregates. Kelly explains, "One pathway disaggregated beta amyloid fibrils, while the other actively packed them into high molecular weight aggregates. But the latter only kicks in when the cell is left with no other options."
The surprise was that very high molecular weight species were actually less toxic than smaller aggregates. "For a long time large protein aggregates were considered the toxic species," explains Cohen. "The fact that cells protect themselves by temporarily storing small fibrils as high molecular weight aggregates marks a clear paradigm shift."
Two proteins controlled by insulin/IGF-1 signaling orchestrate detoxification--HSF-1, which takes care of aggregate break-down, and DAF-16, which mediates formation of safer, super-sized aggregates as debris accumulates. "We assumed that DAF-16 and HSF-1 would do the same job, but they don't. This is extremely exciting because it gives us two unique opportunities to attenuate beta amyloid-mediated toxicity by manipulating the activity of these factors," says Dillin.
New model for neurodegenerative diseases
Half of all people who reach age 85 will likely be affected by Alzheimer's disease, and the onset age – usually around 75 – is almost the same for all sporadic neurodegenerative aggregation diseases. Thus, Salk researchers have developed a model that explains why these disorders diseases occur late in life.
Throughout life, brain cells produce aggregation-prone beta-amyloid fragments that must be cleared. "This process is very efficient when we are young but as we get older it gets progressively less efficient," says Cohen. As the affected individual reaches the seventh decade of life the clearance machineries fail to degrade the continually forming toxic aggregates and the disease emerges. In individuals who carry early onset Alzheimer's-linked mutation, an increased "aggregation challenge" leads to clearance failure and the emergence of Alzheimer's much earlier – usually during their fifth decade.
"It was very satisfying when the biochemical data from Jeffery's lab and genetic results from our lab came together," recalls Dillin. Both scientists are continuing the collaboration by searching for small molecules that delay the aging program and boost protective mechanisms.
Other contributing authors were co-lead author Jan Bieschke, Ph.D., formerly at Scripps and now at Max Delbrueck Center in Berlin, and research assistant Rhonda M. Perciavalle.
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