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Unraveling Alzheimer's Disease Plaques

Could plaque buildup in the brain be the cause rather than the result of the debilitating neurogenerative disorder?

 
SEQUENCE OF EVENTS: Scientists have shown that the plaque found in the brains of deceased Alzheimer's patients may in fact cause the dementia associated with the disorder.

The only way to confirm that someone has Alzheimer's disease, which afflicts an estimated five million Americans, is by peering into their brains and seeing plaque, nestled between the twisted endings of affected nerve cells. Unfortunately, these markers can only be viewed during postmortem investigations.

To date, researchers are unsure whether these bundles (made of a protein fragment called amyloid beta) cause all—if any—of the symptoms of Alzheimer's dementia. Previous work has led to different theories on when plaque forms in the Alzheimer's-ravaged brain: One view holds that they are the cause of the disease, protein deposits develop and disrupt the functions of axons and dendrites (projections originating at the cell body that send and receive messages, respectively). The counter theory posits that they develop as a result of it; affected neurons pump out a surfeit of amyloid precursor protein (the full protein strip from which amyloid beta hails), changing the shape of axons and dendrites (collectively known as "neurites"), eventually leading to disruptive plaque deposits.

Researchers report in Nature that they conducted a study, employing a new visualization technique, on a mouse cortex (the outer layers of the brain) that indicates the plaque may in fact precede disruptions to the neurons' messengers. In addition, they say, it shows that plaque amasses quickly, becoming significant enough within 48 hours to block normal neuronal function and to trigger inflammation (the immune system's first line of defense) within a week.

"When we observed the plaque formation, we didn't see these dystrophic neurites before the plaque," says study co-author Bradley Hyman, director of the Alzheimer's Unit at Massachusetts General's Institute for Neurodegenerative Disease. "Clearly the whole disease, if you think about the entire cortex, plays out really slowly, but every plaque forming event plays out very rapidly."

The researchers also observed that within a day of plaque formation—glial cells (nonneuronal nervous system cells that help support and maintain neurons) race to fill space in order to prevent additional protein buildup. Scientists had previously been unsure of the role of glial cells, that is, whether they slowed or accelerated plaque formation.

To make these observations, Hyman and his colleagues employed a sophisticated new visualization tool called "multiphoton laser confocal microscopy." Essentially, the technology allows the team to section the brain with long-wave light and then drill down and look deep into it without causing physical changes. This way, they were able to track plaque as it formed in mice that were genetically engineered to develop it.

Larry Goldstein, a professor of cellular and molecular medicine at the University of California, San Diego, says that no one suspected that plaque forms so swiftly yet remains so stable (without being cleaned out by the glia). His research and that of others, however, supports the idea of chemical-transporting neurites preceding plaque formation. "I don't think that [the new work] necessarily disagrees with what we're saying. … The regions that we were seeing anomalies in were not regions that normally have plaques," he says. "There are other important cellular changes that happen in Alzheimer's disease–like models that don't have anything to do with plaque, but have to do with transport."

Hyman plans to continue to probe how plaque forms so fast (at least in the cortex) and if there are smaller, plaque complexes that join up to create them. He also plans to explore what happens immediately after plaque accumulates, specifically, how—or if—they disrupt normal neuronal activity. "If you understood what it was that caused that initial precipitation event," Hyman says, "I think that would be a therapeutic target."

PR
An Altar Beyond Olympus for a Deity Predating Zeus 

But archaeologists say they have now found the ashes, bones and other evidence of animal sacrifices to some pre-Zeus deity on the summit of Mount Lykaion, in the region of Greece known as Arcadia. The remains were uncovered last summer at an altar later devoted to Zeus.

Fragments of a coarse, undecorated pottery in the debris indicated that the sacrifices might have been made as early as 3000 B.C., the archaeologists concluded. That was about 900 years before Greek-speaking people arrived, probably from the north in the Balkans, and brought their religion with them.

The excavators were astonished. They were digging in a sanctuary to Zeus, in Greek mythology the father of gods and goddesses. From texts in Linear B, an ancient form of Greek writing, Zeus is attested as a pre-eminent god as early as 1400 B.C. By some accounts, the birthplace of Zeus was on the heights of Lykaion.

After reviewing the findings of pottery experts, geologists and other archaeologists, David Gilman Romano of the University of Pennsylvania concluded that material at the Lykaion altar “suggests that the tradition of devotion to some divinity on that spot is very ancient” and “very likely predates the introduction of Zeus in the Greek world.”

As Dr. Romano remarked, quoting a quip by a friend, “We went from B.C. to B.Z., before Zeus.”

The discovery by the Mount Lykaion Excavation and Survey Project was described last week in interviews and a lecture by Dr. Romano at the Museum of Archaeology and Anthropology at Penn. Mary E. Voyatzis, a project co-director from the University of Arizona, discussed her analysis of the telltale pottery. The project’s third co-director is Michaelis Petropoulos of the Greek Archaeological Service.

Other archaeologists familiar with the discovery tended to agree with Dr. Romano’s interpretation, though they said that continuing excavations this summer and next should reach a more definitive understanding of the altar’s possible pre-Greek use.

“Evidence uncovered certainly points to activity at the altar in prehistoric times,” said Jack Davis, director of the American School of Classical Studies at Athens, who visited the site several times. The project was conducted under the auspices of the American school, but he was not a participant.

“We certainly know that Zeus and a female version of Zeus were worshiped in prehistoric times,” Dr. Davis continued in an e-mail message. “The trick will be in defining the precise nature of the site itself before historical times.”

Ken Dowden, director of the Institute of Archaeology and Antiquity at the University of Birmingham, in England, who was not involved in the research, said that it was not surprising to find the migrating Greeks adapting a sanctuary dedicated to gods of an earlier religion for the worship of their own gods. “Even Christians would on occasion reuse a pagan sanctuary in order to transfer allegiance from the preceding religion to Christianity,” he noted.

“You have some god being worshiped on a mountaintop, and the arriving Greeks have translated the god as ‘Zeus,’ their god of the sky, lightning, weather and so on,” Dr. Dowden said. “It’s going to be pretty close to what they found there, and given the site, it makes very good sense.”

The affinities of Roman gods and goddesses to earlier Greek ones are well known. Jupiter, for example, is a virtual stand-in for Zeus. In antiquity it was perhaps no heresy to have different names for the same deity. The place of Mount Lykaion in practices venerating Zeus is documented in literature and previous archaeological research.

The Greek traveler Pausanias, writing in the second century A.D., described the sanctuary of Zeus on the mountain, 4,500 feet above the rural countryside.

“On the highest point of the mountain is a mound of earth, forming an altar of Zeus Lykaios, and from it most of the Peloponnesus can be seen,” Pausanias wrote. “Before the altar on the east stand two pillars, on which there were once gilded eagles. On this altar they sacrifice in secret to Lykaion Zeus. I was reluctant to pry into the details of the sacrifice; let them be as they are and were from the beginning.”

In “Prolegomena to the Study of Greek Religion,” Jane Ellen Harrison, a British scholar, wrote in 1903, “The Zeus of Homer demanded and received the titbits of the victim, though even these in token of friendly communion were shared by the worshipers.”

The proximity of Mount Lykaion to Olympia, 22 miles northwest, initially attracted Dr. Romano’s attention. Another sanctuary of Zeus, Olympia was a prominent site of the Pan-Hellenic athletic competitions after which current Olympic Games are modeled, and Dr. Romano is an authority on these ancient festivals of sports. His colleagues point out that he is the only archaeologist they know to have a master’s degree in physical education.

At Lykaion, Dr. Romano began excavations of the hippodrome on a high meadow, where Greek athletes competed in horse and chariot races and other sports. Not far above, on the southern summit, meanwhile, the research team mapped the altar site and dug a test trench, under the direction of Arthur Rhon, emeritus professor of anthropology at Wichita State University.

Bones, mostly goats and sheep, were collected. A few bronze artifacts were recovered. Also a seal stone with an image of a bull, suggesting influence at one time from Minoan Crete. Altar stones were burned and cracked from the sacrificial fires.

A geological survey by George Davis of the University of Arizona revealed an ancient fault bordering the altar site on three sides. Could this fault be related to the selection of the site? The region is prone to earthquakes.

Dr. Voyatzis said the potsherds were the most telling finds. Their undecorated style, gray color, the feel of the clay and the way it was fired, she said, were diagnostic of pottery 5,000 years ago.

“You wouldn’t establish a settlement in a stark, fearful place like this,” Dr. Voyatzis said in an interview while visiting Penn. So the pottery, she added, was presumably there as part of ceremonies at the altar.

Like Dr. Voyatzis, Gullog Nordquist of Uppsala University in Sweden was troubled by the jumbled nature of the potsherds in the trench. She said it “raises questions of exactly how it came to be there.”

In an e-mail message last week, Dr. Nordquist, who has visited the site but was not a team member, said that the potsherds “may have belonged to vessels found in graves by people in later times and given to the gods as offerings.” Or they could be remains from an early Bronze Age settlement, although she, too, said “it would be a very inconvenient place to live.”

Dr. Nordquist said that she preferred the explanation that the Lykaion site was indeed used as a cult sanctuary in the time before Zeus. Little is known of the pre-Greek inhabitants, but some scholars think they originated in what is now western Turkey.

“We do not yet know exactly how the altar was first used in this early period, 3000-2000 B.C., or whether it was used in connection with natural phenomena such as wind, rain, lightning or earthquakes, possibly to worship some kind of divinity, male or female, or a personification representing forces of nature,” Dr. Romano said. “But this is what we are thinking at this moment.” 

Are Americans Afraid of the Outdoors?

The electronic world is replacing the natural world for leisure time in rich nations

girls-running-through-field 
NATURAL VERSUS VIRTUAL: Records show that Americans are spending less and less time in the great outdoors.

Americans have been visiting national parks and other natural reserves less and less since 1987, new research confirms. Outdoor pursuits, ranging from camping to hunting, have entered a persistent and growing decline.

"Folks are going out into nature much less and decreasingly every year," says conservation ecologist Patricia Zaradic of the Environmental Leadership Program and co-author of the report published in Proceedings of the National Academy of Sciences USA. "It would take 80 million more visits this year to get the per capita number back up to the level it was in 1987."

Zaradic and her colleague conservation biologist Oliver Pergams of the University of Illinois at Chicago analyzed trends in visits to national parks and forests, state parks, surveys on camping and the number of licenses for activities such as hunting or fishing. All peaked between 1981 and 1991 after 50 years of steady increase and have been declining at roughly 1 percent per year since for an overall drop of as much as 25 percent.

Even a slight increase in the frequency of hiking and backpacking trips did nothing to offset the overall decline. "The average American backpacked once every 12.5 years in the past and [is] now backpacking once every 10 years," Zaradic notes. Similar data on park visits in Japan and Spain showed the same trend. "It looks like, clearly from the Japan data, that this may be an international problem," she says.

The conservationists believe that the electronic world has supplanted the natural world as the leading diversion. Their statistical analysis shows that the increase in video games, movie rentals and other electronic entertainment most closely matches the decrease in camping and park visits, as opposed to income, vacation time, park overcrowding, foreign travel or other potential causes.

But Richard Louv, chairman of the Santa Fe, N.Mex.–based Children and Nature Network and author of Last Child in the Woods, ascribes the change more to increasing school and work pressure on children and parents as well as the rising cost of park visits. Plus, he says, there's the fear factor. "You didn't have the concept of stranger danger [in the past]," Louv says. "If you are raising a generation under protective house arrest, will they have a joyful experience in nature?"

Without such an experience, Louv, Pergams and Zaradic agree that the value of nature might be lost on such children and adults. "If we aren't out in nature, we aren't aware of our human footprint in nature. Then it takes natural disasters like Hurricane Katrina to recognize global warming," Zaradic says. "You don't see the subtle signs, you have to wait for something to hit us over the head."

Pergams and Zaradic plan to tackle the fear issue next. "If fear is a factor, what kinds of fear?" Pergams asks. "Fear of the unknown, fear of animals, fear of getting lost, fear of crime, fear of disease, all kinds of different fears that might come into play and to what extent they might play into the decline." In addition, they hope to compare the results of children's exposure to "virtual" nature online or on television with the real thing.

The solution may be as simple as getting kids into the woods or other natural areas in the company of parents, grandparents or other relatives. "This isn't a bitter pill," Louv says. "In order to give kids some semblance of unorganized activity in nature, we're probably going to have to organize a lot of it. It's a paradox we'll have to deal with with a sense of humor."

Biologist Edward O. Wilson argues that humans are hardwired for biophilia, or a love of wild plants and animals, and that putting them back in touch with the environment could resurrect that feeling. "We undervalue the playing in the mud kind of experience," Zaradic says. "Which, it turns out, provides a lot of education."

Putting more nature back into humanity's urban environments might not hurt either. "Green urbanism is about efficiency, saving energy. That's important but ultimately it's kind of boring," Louv says. "Biophilic design is the idea that when we design nature into our cities really interesting things begin to happen."

Net Benefits: Bed Netting, Drugs Stem Malaria Deaths

Proactive African countries see fewer children felled by the mosquito-borne disease

Four African countries saw significantly fewer childhood deaths from malaria after distributing insecticide-treated bed nets and combination drug therapy, according to a new report released by the World Health Organization (WHO).

WHO recommends that malaria-stricken countries distribute so-called long lasting insecticidal nets to protect sleepers from mosquitoes carrying the malaria parasite as well as a cocktail of medicines (artemisinin-based combination therapy, or ACT) designed to treat drug-resistant malaria (Plasmodium falciparum), a growing problem.

To find out how the recommended malaria strategy is working, WHO agents reviewed health records from 30 rural hospitals and clinics for the past seven years in the countries that were first to dispense the nets and ACT drugs. They found that from 2005 to 2007 malaria deaths in children under age five had declined 51 percent in Ethiopia, 66 percent in Rwanda, 33 percent in Zambia and 34 percent in Ghana, the latter of which was the only one of the four nations to see a drop in deaths from nonmalarial disease as well.

Malaria is blamed for at least a million deaths a year, most them young children in sub-Saharan Africa. Preventive drugs alone have failed to stave off the disease, because they are expensive and must be taken continually to be effective—and, even then, sometimes are impotent against resistant strains; it has also proved difficult to target with vaccines.

"It appears that dramatic reduction in malaria mortality can be achieved quickly and may enable many African countries to make rapid progress [in] child survival [rates]," the study authors wrote.

The report, written for the Geneva, Switzerland–based Global Fund to Fight AIDS, Tuberculosis and Malaria, a major backer of malaria control efforts worldwide, attributed the steeper declines in Ethiopia and Rwanda to the number of treated nets distributed in 2005 and 2006.

Languages Burst Forth Rapidly

Words Rush Forth
Words Rush Forth
One group's desire to differentiate itself from another may have prompted the sudden development of new languages.

New languages often evolve quickly, in a sudden burst of new words coined as groups of people strive to describe the world around them, says an international team of researchers.

Quentin Atkinson from the UK's University of Oxford and colleagues report their findings today in the journal Science.

Scientists debate the evolution of language in a way that parallels arguments in biological evolution.

Do most changes come about slowly and gradually or rapidly within relatively short spans of time?

To answer this question, the researchers studied sets of basic vocabulary from 490 different languages in Europe, Asia and Africa. They used the same kind of computer program biologists use to create family trees to track the appearance of related words and so trace the evolution of new languages from older ones.

"We compared things like the words for body parts, words about kinship, colors and other basic words," said researcher Simon Greenhill, a Ph.D. candidate from the University of Auckland in New Zealand.

Their results showed many of the novel words that make up new languages appear in an initial burst over a relatively short period of time.

"We're probably talking generations," said Greenhill, "maybe around 100 years."

In Bantu languages from Africa, for example, more than 30 percent of vocabulary differences between languages arose at or around the time that they split off from each other, say the researchers.

In the languages of Indonesia, Polynesia and Papua New Guinea, the rush of new words accounted for about 10 percent of differences. Several factors might account for the tendency of new languages to evolve this way, the researchers say.

For example, the changes might reflect the need of one emerging group of people to differentiate itself from another.

"Some people might exaggerate the differences between their languages to reinforce their groups," said Greenhill.

In other cases, small groups of people who become isolated might develop new ways of speaking based on the vocal quirks of their founders, he says.

For example, this might have played a part in the evolution of Polynesia's 30 or so languages, which emerged over approximately 1200 years, the researchers suggest.

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