Bio Screening Industry News

Research into Alzheimer’s disease seems an unlikely approach to yield a better way to fight urinary tract infections (UTIs), but that’s what scientists at Washington University School of Medicine in St. Louis and elsewhere recently reported.

One element links the disparate areas of research: amyloids, which are fibrous, sticky protein aggregates. Some infectious bacteria use amyloids to attach to host cells and to build biofilms, which are bacterial communities bound together in a film that helps resist antibiotics and immune attacks. Amyloids also form in the nervous system in Alzheimer’s disease, Parkinson’s disease and many other neurodegenerative disorders.

To probe amyloids’ contributions to neurodegenerative diseases, scientists altered potential UTI-fighting compounds originally selected for their ability to block bacteria’s ability to make amyloids and form biofilms. But when they brought the compounds back to UTI research after the neurology studies, they found the changes had also unexpectedly made them more effective UTI treatments.

“Thanks to this research, we have evidence for the first time that we may be able to use a single compound to impair both the bacteria’s ability to start infections and their ability to defend themselves in biofilms,” says senior author Scott J. Hultgren, Ph.D., the Helen L. Stoever Professor of Molecular Microbiology at Washington University.

The findings were reported online in Nature Chemical Biology.

The National Institutes of Health has estimated that over 80 percent of microbial infections are caused by bacteria growing in a biofilm, according to Hultgren. Scientists in Hultgren’s laboratory have worked for decades to understand the links between biofilms and UTIs.

“UTIs occur mainly in women and cause around $1.6 billion in medical expenses every year in the United States,” says co-lead author Jerome S. Pinkner, laboratory manager for Hultgren. “We think it’s likely that women who are troubled by recurrent bouts of UTIs are actually being plagued by a single persistent infection that hides in biofilms to elude treatment.”

Co-lead author Matthew R. Chapman, Ph.D., now associate professor of molecular, cellular and developmental biology at the University of Michigan, was a postdoctoral fellow in Hultgren’s lab in 2002 when he discovered that the same bacterium that causes most UTIs, Escherichia coli, deliberately makes amyloids. The amyloids go into fibers known as curli that are extruded by the bacteria to strengthen the structures of biofilms.

To treat UTIs, Hultgren’s lab has been working with Fredrik Almqvist, Ph.D., a chemist at the University of Umea in Sweden, to develop compounds that block bacteria’s ability to make curli, disrupting their ability to make biofilms and leaving them more vulnerable to antibiotics or immune system attacks. Almqvist recently suggested altering a group of the most promising curli-blockers to see if they could also block the processes that form amyloids in Alzheimer’s disease.

The alterations worked: In laboratory tests, the new compounds prevented the protein fragment known as amyloid beta from aggregating into amyloid plaques like those found in the brain in Alzheimer’s disease. When scientists took the new compounds back to a mouse model of UTIs, though, they received a surprise. The altered compounds were better at reducing the virulence of infections, inhibiting not only curli formation but also the formation of a second type of bacterial fibers, the pili.

“Pili aren’t made of amyloids, but they are essential to both biofilms and to the bacteria’s ability to initiate an infection,” Hultgren says.

Hultgren and colleagues are already developing even more potent infection and amyloid fighters, screening a library of thousands of chemicals similar to the most promising compounds from the study.

Chapman cautions that it’s too early to tell which, if any, of the compounds will be helpful in treating neurodegenerative diseases.

“Much neurodegenerative drug development has focused on ways to break up amyloids or prevent them from forming, but because amyloids may also be an important part of normal cellular physiology, we need to identify molecules that will target only the toxic amyloid state,” he says.

Cegelski L, Pinkner JS, Hammer ND, Cusumano CK, Hung CS, Chorell E, Aberg V, Walker JN, Seed PC, Almqvist F, Chapman MR, Hultgren SJ. Small-molecule inhibitors target Escherichia coli amyloid biogenesis and biofilm formation. Nature Chemical Biology, published online.

Funding from the Swedish Natural Science Research Council, the Knut and Alice Wallenberg Foundation, the National Institutes of Health and the Burroughs Wellcome Fund supported this research.

Source
Washington University in St. Louis

Researchers investigating the causes of Alzheimer’s disease have been left puzzled by data showing that the antihistamine dimebolin, a drug with promising activity in improving Alzheimer’s symptoms, actually seems to increase levels of the toxic protein beta amyloid.

For years it has been thought that the degeneration of nerves seen in Alzheimer’s disease was a result of exposure to the protein fragment beta amyloid. In healthy brains the fragments are broken down and eliminated, while in Alzheimer’s they accumulate to form insoluble plaques.

Results from a Phase II clinical trial reported last year found that dimebolin was around two-and-a-half times more effective than current medicines such as Pfizer and Eisai’s Aricept (donepezil) in improving cognition and memory in Alzheimer’s patients.

The drug’s activity in Alzheimer’s was discovered serendipitously when Russian scientist Sergey Bachurin was screening a number of compounds that could block both cholinesterase and NMDA (N-methyl-D-aspartic acid) - the targets for the current generation of Alzheimer’s treatments. It is currently being tested in Phase III clinical trials by US biopharmaceutical firm Medivation in collaboration with Pfizer.

However, results from the latest experiments in mice, reported at a meeting in Vienna last week, indicate that dimebolin actually appears to increase levels of beta amyloid - undermining the idea that the plaques themselves are toxic. The results also raise questions about many of the other drugs that are being developed to treat the disease.

Samuel Gandy of the Mount Sinai School of Medicine in New York, who carried out the experiments, told Chemistry World that the findings were surprising. ‘Conventional wisdom in the field, regardless of one’s position on ‘the amyloid hypothesis’, is that an amyloid benefit would mean amyloid-lowering.’

‘The latest findings don’t mean we should toss amyloid,’ he says. ‘But we should be prepared to consider unconventional possibilities.’

Clive Ballard, research director of the Alzheimer’s Society in the UK, concurs with that view. ‘The data tie in with an alternative hypothesis, namely that other forms of amyloid - such as soluble amyloid oligomers - may actually be more neurotoxic than insoluble plaques, he says.

One school of thought is that plaques may in fact represent a protective mechanism in which the body sequesters toxic forms of amyloid to render them harmless. ‘The Gandy research may be showing that dimebolin is driving this process, stimulating conversion of amyloid strands into a non-toxic form,’ suggests Ballard.

The problem for the pharmaceutical sector is that some of the new drugs coming through late-stage clinical testing, including Wyeth and Elan Pharmaceuticals’ much-anticipated antibody bapineuzumab are designed to break down the plaques.

Gandy believes researchers should also be looking at what is going on with amyloid inside nerve cells, rather than the external manifestations of amyloid processing.

‘We should perhaps be paying more attention to intracellular oligomers,’ he says. ’There are mice models with elevated intraneuronal oligomers and these show impaired functions, so this is certainly an avenue worth exploring.’

Other drugs in the pharmaceutical pipeline, such as the gamma secretase inhibitor class being developed by Eli Lilly, Bristol-Myers Squibb and others might lower intracellular beta amyloid levels.

‘However, we might need different drugs from the ones that we have, all of which are optimised to lower beta amyloid levels in the cerebrospinal fluid and interstitial fluid,’ says Gandy.

Source: rsc.org

Elderly people with mild cognitive losses are at a heightened risk of progressing to Alzheimer’s disease if they have a combination of telltale compounds in their spinal fluid, researchers report in the July 22/29 Journal of the American Medical Association.

By testing for a shortage of a sticky compound called amyloid-beta in the spinal fluid and for excess amounts of two kinds of a protein called tau, the scientists could identify people at greatest risk.

The test isn’t foolproof, and a positive reading still warns of a disease for which there is no cure. But scientists are heartened by this and earlier studies (SN: 9/20/03, p. 179)because Alzheimer’s disease is difficult to foresee and its early symptoms are often mistaken for routine cognitive losses caused by aging.

Niklas Mattsson of a Gothenburg University-affiliated hospital in Mölndal, Sweden, and an international group of scientists recruited 750 elderly people in Europe and the United States from 1990 to 2007. At the time of enrollment, the volunteers had mild cognitive impairment — a loss of memory or other mental faculties — that wasn’t attributable to aging alone but fell short of Alzheimer’s disease. Each volunteer contributed a cerebrospinal fluid sample by undergoing a spinal puncture. The participants, average age 69, were monitored for about three years during the study.

Those who developed Alzheimer’s disease were more likely to have had less amyloid-beta or more tau in their spinal fluid than those who didn’t develop Alzheimer’s. People who had both low amyloid-beta and high tau levels were five times as likely to develop Alzheimer’s disease during the study as were those with normal spinal fluid profiles, Mattsson says.

The screening test correctly predicted incipient Alzheimer’s disease 83 percent of the time. Studies that track elderly patients longer may show an increased accuracy rate because patients whose spinal fluid tested positive may develop Alzheimer’s disease later, says Ronald Petersen, a neurologist at the Mayo Clinic in Rochester, Minn.

Since spinal fluid bathes the entire central nervous system, its components can serve as markers for what’s going on in the brain. Although the precise biological course of Alzheimer’s is murky, many scientists theorize that amyloid-beta accumulates in the brain early in the disease process, leaving less to circulate in the spinal fluid, Petersen says. Later, tau is released from dying brain cells into the spinal fluid, increasing tau levels there.

Roughly half of all elderly people with mild cognitive impairments later develop Alzheimer’s disease, says Mattsson, a physician and neuroscientist. Currently available drugs treat only Alzheimer’s symptoms, not the disease.

By fine-tuning this screening test, Mattsson, Petersen and others are planning for the day when other research teams develop drugs to arrest or reverse the brain damage that marks the disease. There are up to 100 such experimental Alzheimer’s drugs currently in development, Petersen says. “Almost every major pharmaceutical house has a program for Alzheimer’s.”

If such medications become available, accurate diagnosis will become paramount in determining how to prescribe them, Mattsson says. “It’s very important to interfere with the disease as early as possible, and this is where the diagnostic test comes in.” Screening for changes in amyloid-beta and tau in drug trial participants might also indicate which medications are thwarting the disease process, Mattsson says.

Source: Sciencenews.org

SOURCE Cognition Therapeutics Inc.

BY NYSSA SKILTON

MEDICAL REPORTER

18/11/2008

CSIRO scientists have developed a way to screen for compounds that can inhibit the progression of Alzheimer’s disease.

The system involves using live yeast and a protein called Abeta fused to a fluorescent green protein, which comes from jellyfish.

The scientists, working within CSIRO’s Preventive Health Flagship, published their findings in the latest edition of the Journal of Alzheimer’s Disease.

Alzheimer’s disease is the fourth leading cause of death in people older than 65 and there is no cure known to science.

It is thought to be the result of a loss of neurons in the brain, caused by a process in which toxic forms, known as multimers, of the small Abeta protein are created.

Lead author Ian Macreadie said the scientists had discovered a ‘’rapid screening system'’ to identify inhibitors of this process.

‘’Compounds that inhibit the formation of the toxic multimers may lead to the prevention or delay of the disease,'’ Dr Macreadie said.

‘’The yeast trial we developed could lead to the discovery of new agents which may prove useful in preventing or delaying the onset of Alzheimer’s disease.'’

The researchers tested their screening system using folate, a nutrient known to protect against Alzheimer’s disease. They found that the folate made the yeast with the jellyfish protein greener.

The green colour signifies that the additive, in this case the folate, has stopped the Abeta protein from changing into its toxic forms.

‘’The greener the better,'’ Dr Macreadie said. ‘’We’re interested in finding not just folate, but many existing compounds and novel compounds that may be helpful in [combating] Alzheimer’s.'’

The researchers have already screened hundreds of compounds in the search for Alzheimer’s inhibitors. They plan to screen foods to identify nutrients they may use to enrich foods to protect consumers.

CSIRO scientists have developed a new system to screen for compounds that can inhibit one of the processes that takes place during the progression of Alzheimer’s disease.

In a paper published in the Journal of Alzheimer’s Disease, folate is shown to be beneficial in the screening system.

Lead author, CSIRO’s Dr Ian Macreadie says folate is already well known to have a protective effect against Alzheimer’s disease which is believed to be caused by the loss of neurons in the brain due to a process whereby toxic multimers of a small protein called Aβ are formed.

“However, a team of scientists working within CSIRO’s Preventative Health Flagship has discovered a rapid screening system to identify inhibitors of this process. Compounds that inhibit the formation of the toxic multimers may lead to the prevention or delay of the disease,” Dr Macreadie says.

“Although many other research groups and drug companies around the world are trying to find compounds that act in the same way, the advance by the Flagship team involves using live yeast with the Aβ protein fused to a green fluorescent protein that comes from jellyfish.

“The significance of this development is that the yeast trial we developed could lead to the discovery of new agents which may prove useful in preventing or delaying the onset of Alzheimer’s disease.”

Currently Alzheimer’s disease is an incurable illness and the fourth leading cause of death in people aged 65 years and over.

Although folate is abundant in foods like leafy green vegetables, pulses and liver, CSIRO studies have shown that many Australians do not consume enough folate to benefit from its ability to prevent cell damage. Folate levels can, however, be readily restored by dietary folate supplementation.