New plaque protein identified in brains of people with Alzheimer's disease
Alzheimer's: New Lesion Found in Diseased Brains
Alzheimer-related genetic factor linked to brain damage in boxers
Lancet 12 July 97 Marilynn LarkinA newly discovered protein in plaque-like lesions in the brains of people with Alzheimer's disease (AD) seems abundant, widespread, and "highly specific" for the disease, says John Trojanowski, director of the University of Pennsylvania's Alzheimer's Disease Center (Philadelphia, USA). He suspects that the protein, AMY117, may play "a crucial role in the development and progression" of the dementing illness.
Trojanowski's team were exploring components of neurofibrillary tangles in brains from patients with AD with a panel of 59 monoclonal antibodies developed to study tangles. Four antibodies did not recognise hyperphosphorylated tau, a key protein in the tangles, but instead reacted with a protein that was in numerous plaque-like lesions. "We thought, 'how boring--another amyloid plaque-associated protein', and we shoved it off to the side", Trojanowski recalls. But the plaques containing AMY117 did not colocalise with those containing þ-amyloid. "They were in the same cortical and subcortical gray-matter regions, but they weren't the same lesions."
The team found that AMY117-positive plaques were "abundant" in the brains of sporadic cases of AD and in brains from people with Down's syndrome, but "rare or absent" in brains of controls and of other neurodegenerative diseases (Am J Pathol 1997; 151: 69‚80). The new lesions "may be even more specific to AD than amyloid plaques", notes Trojanowski, who is now trying to clone the gene for AMY117.
If this "illuminating and potentially very significant" finding is confirmed, notes Zaven Khatchaturian, who is director of the Alzheimer's Association Ronald and Nancy Reagan Research Institute (Chicago, IL, USA), it could "provide fresh targets for therapies and give us a new diagnostic marker for the disease".
Science July 10, 1997 Wade RoushFor years, researchers praying for clues that might lead to a new treatment for Alzheimer's disease have had two congregations to choose from: the "BAPtists," who attribute the disease mainly to the beta-amyloid protein (sometimes known as BAP) found in plaques that riddle the brains of Alzheimer's patients, and the "Tauists," who suspect that the misbehavior of a neuronal protein called tau is more central. Now, with the detection of a third type of lesion that has apparently lain hidden ever since Alois Alzheimer began studying the disease 90 years ago, a new sect may be in the making.
The new lesions are known for now as "AMY plaques," because they were initially mistaken for amyloid plaques. They appear to be nearly as widespread in the brains of Alzheimer's patients as the more familiar plaques and tangles of tau proteins, according to a team led by neuropathologist John Trojanowski and neuroscientist Virginia Lee at the University of Pennsylvania School of Medicine in Philadelphia, who report their work in the July issue of the American Journal of Pathology. That means the AMY plaques could represent an unrecognized cause of the dreaded memory-depleting disease, which strikes 5% of people over age 65.
"I feel very excited about it," says neuroscientist Zaven Khachaturian, director of the Alzheimer's Association's Ronald and Nancy Reagan Research Institute in Chicago. "This opens new vistas for us in terms of conceptualizing what's happening in the disease, and it may even give us new diagnostic tools and new targets for treatment." But he and others note that this promise won't be realized soon, because researchers still aren't certain how or even whether the familiar amyloid plaques and neurofibrillary tangles cause neuronal deterioration.
The Penn researchers discovered the new lesions by accident while trying to learn more about the tau protein, which is normally found inside neurons but congeals in extracellular masses in the brains of Alzheimer's patients. Two years ago, Trojanowski and Lee reported from studies of biopsied and autopsied tissue that tau collects this way when phosphatases, enzymes that remove excess phosphate groups from tau, somehow fail to do their job (Science, 10 February 1995, p. 793).
To learn whether trouble at tau's phosphate-binding sites contributes to this problem, Marie Luise Schmidt, a researcher in Trojanowski and Lee's laboratory and the study's lead author, reviewed a set of 59 new antibodies designed by Lee to recognize and bind to these sites. While testing the antibodies on tissue slices from Alzheimer's brains, however, Schmidt found that four of them--especially one called AMY 117--didn't bind to tau at all, but sought out plaques instead.
The team suspected that the purified proteins used to create the antibodies weren't pure--that they contained molecules from amyloid plaques, a glitch they had encountered before. But when Schmidt stained brain slices using both AMY 117 and an antibody to amyloid, she was astonished to find that the two antibody types gravitated to two different sets of plaques--one of which had never before been glimpsed. The new lesions resemble the amyloid plaques from the outside, but inside they lack the core of beta-amyloid protein that traditional staining techniques recognize. So the proteins used to make the antibodies must have been contaminated after all--but with proteins from the AMY plaques, not the amyloid plaques. The existence of the new lesions "couldn't have been suspected without these new antibodies," says Trojanowski.
All 32 of the Alzheimer's brains the team examined exhibited the new lesions, usually close to, but not overlapping, the amyloid plaques. That means Alzheimer's researchers now have an entirely new set of pathological mechanisms to explore. Explains Trojanowski: "It could be that if you sweep away amyloid plaques and tangles and still have these AMY plaques, you would only be getting rid of two-thirds of the symptoms."
The Penn team is currently purifying the AMY 117-binding protein with the goal of cloning the gene encoding it. That could eventually lead to an improved means of diagnosing Alzheimer's based on detecting the protein in the blood or cerebrospinal fluid, and perhaps even to a way of blocking the formation of new plaques.
But will Alzheimer's researchers welcome this new denomination to their increasingly ecumenical field? "Heavens, yes," says neuromolecular biologist Marcelle Morrison-Bogorad, associate director of the Neuroscience and Neuropsychology of Aging program at the National Institute on Aging. "The more angles we have, the closer we'll be to understanding what Alzheimer's actually is."
Associated Press July 9, 1997CHICAGO -- A gene linked to Alzheimer's disease might also explain why some boxers suffer permanent brain damage and others can take blows to the head for years without serious effects, researchers say. The finding, described as preliminary, raises questions of whether athletes should be screened before being allowed to box, the researchers said.
Previous studies have shown that head injuries increase the risk of Alzheimer's, especially in carriers of the implicated gene, called APOE-4. The gene is present in about 20 percent of people. A study in Wednesday's Journal of the American Medical Association suggests that boxers who inherit APOE-4 -- especially those who have been punched a lot -- are predisposed to developing chronic traumatic brain injury, a disorder characterized by memory loss and reduced mental capacity.
The findings have "extraordinary ramifications for the regulation of health and safety in boxing and other high-risk sports," wrote the authors, led by Dr. Barry D. Jordan, a neurologist who did the research while at Cornell University in New York. He is now at Charles J. Drew University of Medicine in Los Angeles.
The presence of APOE-4 "would not necessarily preclude a boxer from participation but could be an indication to minimize or more strictly limit exposure to the sport," the researchers said. Jordan's findings were first presented in May at a conference in Aruba on boxing medicine and were reported by The Associated Press. Jordan, an adviser to the Association of Boxing Commissions, and his colleagues performed tests on 30 professional boxers in the New York area. They also did neurologic tests to determine the extent of brain injury. They found that three fighters with severe chronic traumatic brain injury were all carriers of the protein.