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Little Proteins, Big Clues After a Quarter of a Century, the Amyloid Hypothesis for Alzheimer’S Disease Is Reconnecting to Its Roots in Prion Research

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Little Proteins, Big Clues After a Quarter of a Century, the Amyloid Hypothesis for Alzheimer’S Disease Is Reconnecting to Its Roots in Prion Research ALZHEIMER’S DISEASE OUTLOOK SIMON FRASER/JAMES KING-HOLMES/SCIENCE PHOTO LIBRARY PHOTO KING-HOLMES/SCIENCE SIMON FRASER/JAMES At autopsy, the brains of Alzheimer’s patients (right) are filled with amyloid plaques, reminiscent of the plaques seen in the brains of animals with scrapie (left). AMYLOID Little proteins, big clues After a quarter of a century, the amyloid hypothesis for Alzheimer’s disease is reconnecting to its roots in prion research. BY JIM SCHNABEL It is easy to forget how recently Alzheimer’s resembling those seen in scrapie, often sur- disease entered the public consciousness. rounded by dying neurons and their twisted n September 1984, a group of prominent For many decades after it first appeared in the axons and dendrites. When doused with Congo researchers from around the world met in medical literature, the term referred only to red, a standard pathology stain, and illumi- Scotland to discuss a disease that afflicted an obscure, early onset form of dementia. nated with polarized light, the Alzheimer’s Isheep and goats. What we now know as common, late-onset plaques — just like scrapie plaques — displayed Scrapie, as they called it, was important Alzheimer’s was then called ‘senile dementia’ — an apple-green shimmer, a prismatic sign of the for more than agricultural reasons — it was and it was so prevalent among the elderly that hydrogen bonds that held their fibrils tightly also the most easily studied example of an it hardly seemed worth classifying as a disease together. Protein aggregates that had this emerging class of diseases that destroyed (see ‘A problem for our age’, page S2). peculiar property were called amyloids. the brain. The illnesses jumped infectiously Earlier that year George Glenner, an amy- from animal to animal, yet yielded no trace of THE MYSTERY PROTEIN loid researcher at the University of California, a virus or other microorganism. One big clue It is also easy to forget that at the dawn of San Diego, reported isolating a small protein was that these diseases left behind insoluble Alzheimer’s research, the disease was suspected from amyloid deposits in brain blood vessels in clumps, or plaques, made from millions of of being a prion disease — we tend to think of people with Alzheimer’s disease. Was the pro- tiny fibrils, each of which comprised hun- the connection between prions and Alzheimer’s tein embedded in Alzheimer’s brain plaques the dreds or thousands of proteins. A striking as being much more recent. In late 2010, for same as the one in Glenner’s vascular deposits? new hypothesis proposed that these fibrils example, a team led by Mathias Jucker at the Or was it more like the scrapie protein? and their plaques marked the toxic passage of University of Tübingen, Germany, reported Masters and Beyreuther, at their dinner in infectious proteinaceous particles, or prions. that they could, in essence, transmit Alzhei- Scotland, agreed to collaborate to find out, and On the first night of the conference, sev- mer’s-type brain pathology in a prion-like their partnership probably did more than any eral researchers gathered for dinner. Among manner by injecting Alzheimer’s brain matter other to launch modern Alzheimer’s research them were Colin Masters, a neuropathologist into the bodies of mice (Eisele, Y. S. et al. Sci- and its central idea: the amyloid hypothesis. from the University of Western Australia, and ence 330, 980–982, 2010). Such findings have Masters had already painstakingly puri- Konrad Beyreuther, a protein-sequencing contributed to a major rethink of the cause of fied a quantity of Alzheimer’s amyloid, in expert from the University of Cologne in Alzheimer’s disease. But this rethink is partly a process akin to bomb-grade uranium Germany. Masters began telling Beyreuther a renaissance because, as the story of Masters enrichment. When about a human disease that featured plaques and Beyreuther’s early interest in Alzheimer’s a sample arrived in NATURE.COM like those seen in scrapie and seemed to be very reminds us, the prion connection is not new. Germany, Beyreuther research the role common. It was called Alzheimer’s disease. “It was there at the beginning,” says Masters. and his colleagues broke of amyloid-β in “Until then I had never heard of Alzheimer’s As Masters knew in 1984, autopsies of it down with formic Alzheimer’s disease disease,” Beyreuther recalls. Alzheimer’s patients revealed brain plaques acid and sifted through go.nature.com/qpcyez S12 | NATURE | VOL 475 | 14 JULY 2011 ALZHEIMER’S DISEASE OUTLOOK the debris to find the smallest stable protein. models that overexpressed APP — lacked the This turned out to be a tiny peptide of roughly heavy neuronal losses and cognitive decay asso- 40 amino acids, and Masters and Beyreuther ciated with the human disease. “These models called it A4. Sequencing A4 showed that it was have some cognitive decline, but it’s not as much not the scrapie protein, or indeed anything like as a person with full-blown Alzheimer’s disease, it, but was essentially the protein Glenner had by any stretch,” says Harvard neurologist Bruce isolated from blood vessels. Yankner, a long-time Alzheimer’s researcher. Beyreuther’s team quickly determined that Some researchers suspected that mice, with A4 is a fragment of a much larger neuronal their small brains and short lives, cannot accu- EYE OF SCIENCE/SCIENCE PHOTO LIBRARY EYE OF SCIENCE/SCIENCE PHOTO protein, amyloid precursor protein (APP). rately model such a slow-burning, big-brain They found the gene that encodes APP on disease. But another possibility, which gained chromosome 21. This was a big clue, as people currency in the late 1990s, is that amyloid-β with Down’s syndrome, who have an extra copy plaques are not the real drivers of dementia. of chromosome 21, were known to develop Autopsy studies showed, for example, that the Alzheimer’s-like brain plaques by 40 years of progress of Alzheimer’s dementia does not cor- age. The overproduction of APP and A4 was relate well with the development of plaques. now revealed as the likely reason for the plaques As Beyreuther and Masters had initially in Down’s syndrome — and probably in Alzhei- observed, the plaques become dense in the brain mer’s disease too. long before any signs of cognitive decline. Unfortunately, the major pharmaceutical TOO MUCH AGGREGATION companies had already placed their bets on Other Alzheimer’s investigators readily Like prions (above), amyloid-β might spread in an the amyloid-β plaque hypothesis, and numer- pursued the APP lead. But three other impor- infectious manner within tissues. ous drug-development programs would go on tant clues from this initial burst of research to fail in clinical trials. But in the meantime, by Beyreuther and Masters would be almost and one of their first acts was to rename the A4 a small group of researchers had begun to entirely overlooked for most of the next decade. protein amyloid-β, where the β referred to the develop a new hypothesis that encompassed The first was an observation by Beyreuther classic β-sheet molecular structure of amyloids. Alzheimer’s and a variety of other amyloid- about the forms of A4 in different solvent They also put much less emphasis on the forming diseases. mixes. He noted the presence of stable clusters, original prion connection. “Some of these or oligomers, made of two, four or more copies young guys who came after us didn’t seem to OLIGOMERS REVISITED of A4. So strong was the peptide’s tendency to know what a prion was,” says Masters. The genetic evidence made it almost certain that form these oligomers that in certain solutions, Even so, they seemed to move swiftly the aggregation of amyloid-β somehow leads dimers made of two copies of A4 were more towards an understanding of how amyloid-β to Alzheimer’s disease. The fibrils in plaques prevalent than monomers. causes Alzheimer’s disease. In the early and were the most obvious type of aggregate, and The second clue was that full-length A4 is mid-1990s, in-vitro studies indicated that therefore the most obvious suspect. Only extremely prone to aggregate. After obtaining amyloid-β becomes toxic to neurons when it after the plaque hypothesis began to fail did the full A4 sequence, Beyreuther began to syn- begins to aggregate. Genetic studies of families researchers return to the other aggregates: the thesize various lengths of it in his lab, including with early onset Alzheimer’s disease detected amyloid-β oligomers first seen by Beyreuther a series that started at the 42nd (and terminal) mutations within the gene that encodes APP, and his colleagues in Cologne. amino acid of its longest variant and worked and analysis of one of these mutant APP In the early and mid-1990s, Charles Glabe towards the opposite end. “When we came genes found that it causes a sevenfold over- at the University of California, Irvine, and close to the end of the peptide and took it off the production of amyloid-β (see ‘Finding risk fac- Dennis Selkoe at Harvard University reported resin, we saw it getting aggregated,” he remem- tors’, page S20). Transgenic mice that overpro- finding oligomers in experiments with bers. “I thought ‘Mein Gott, it’s snowing!’ It was duced human APP and amyloid-β developed amyloid-β. They saw them as briefly existing aggregating so quickly. It was horrible.” plaques resembling those seen in Alzheimer’s intermediates on the way to disease-causing The third clue came after Beyreuther and disease, and their behaviour in standard tests fibrils, rather than fully fledged drivers of Masters raised the first antibodies to A4 and suggested some cognitive deficits.
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