Posts tagged alzheimer’s disease
Articles and news from the latest research reports.
A molecular chain reaction in Alzheimer’s disease
Researchers at Lund University in Sweden have identified the molecular mechanism behind the transformation of one of the components in Alzheimer’s disease. They identified the crucial step leading to formations that kill brain cells.
Alzheimer’s disease is associated with memory loss and personality changes. It is still not known what causes the onset of the disease, but once started it cannot be stopped. The accumulation of plaques in the brain is widely considered a hallmark of the disease. The key discovery identified the chemical reaction that causes the plaques to grow exponentially.
Amyloid beta, a protein fragment that occurs naturally in the fluid around the brain, is one of the building blocks of plaques. However, the processes leading from soluble amyloid beta to the form found in the plaques, known as amyloid fibril, have not been known. In the very early part of the process, two protein fragments can create a nucleus that then grows into a fibril.
In solution this is a slow process, but the rate can be enhanced on surfaces. The current study shows that fibrils present a catalytic surface where new nuclei form and this reaction increases the speed of the process. As soon as the first fibrils are formed, amyloid-beta fragments attach at its surface and form new fibrils that subsequently detach.
This process is thus self-perpetuating, and autocatalytic, and the more fibrils are present, the quicker the new ones are created, says Sara Snogerup Linse, Professor of Chemistry at Lund University and one of the researchers behind the study.
The findings also show that the chemical reaction on the fibril surface creates cell-killing formations. It is hoped that the research could lead to a new type of medication targeting early stages of the disease in the future.
The results have emerged from several years of laboratory work by Professor Snogerup Linse and her colleague in Lund, Erik Hellstrand, including development of extensive methods to obtain amyloid beta in highly pure form and to study its transformation in a highly reproducible manner. Additional methodology based on isotope labelling and spin filters was developed to monitor the surface catalysis and pin-point the origin of the forms that kill brain cells. The collaboration with the theoretical group and cell biologists at Cambridge University has been absolutely crucial for all the findings.
(Source: alphagalileo.org)
New chemical approach to beat Alzheimer’s disease
Scientists at the University of Liverpool and Callaghan Innovation in New Zealand have developed a new chemical approach to help harness the natural ability of complex sugars to treat Alzheimer’s disease.
The team used a new chemical method to produce a library of sugars, called heparan sulphates, which are known to control the formation of the proteins in the brain that cause memory loss.
Chemically produced in the lab
Heparan sulphates are found in nearly every cell of the body, and are similar to the natural blood-thinning drug, heparin. Now scientists have discovered how to produce them chemically in the lab, and found that some of these sugars can inhibit an enzyme that creates small proteins in the brain.
These proteins, called amyloid, disrupt the normal function of cells leading to the progressive memory loss that is characteristic of Alzheimer’s disease.
Professor Jerry Turnbull, from the University’s Institute of Integrative Biology, said: “We are targeting an enzyme, called BACE, which is responsible for creating the amyloid protein. The amyloid builds up in the brain in Alzheimer’s disease and causes damage. BACE has proved to be a difficult enzyme to block despite lots of efforts by drug companies.”
“We are using a new approach, harnessing the natural ability of sugars, based on the blood-thinning drug heparin, to block the action of BACE.”
Dr Peter Tyler, from Callaghan Innovation, added: “We have developed new chemical methods that have allowed us to make the largest set of these sugars produced to date. These new compounds will now be tested to identify those with the best activity and fewest possible side effects, as these have potential for development into a drug treatment that targets the underlying cause of this disease.”
Current treatments only help symptoms
There are more than 800,000 people in the UK, and 50,000 in New Zealand living with dementia. Over half of these have Alzheimer’s disease, the most common cause of dementia. The cost of these diseases to the UK economy stands at £23 billion, more than the cost of cancer and heart disease combined. Current treatments for dementia can help with symptoms, but there are no drugs available that can slow or stop the underlying disease.
Neurons die in Alzheimer’s because of faulty cell cycle control before plaques and tangles appear
The two infamous proteins, amyloid-beta (Aβ) and tau, that characterize advanced Alzheimer’s disease (AD), start healthy neurons on the road to cell death long before the appearance of the deadly plaques and tangles by working together to reactivate the supposedly blocked cell cycle in brain cells, according to research presented on Dec. 17 at the American Society for Cell Biology’s Annual Meeting in San Francisco.
Working in a mouse model of AD, George Bloom, PhD, of the University of Virginia (UVA) reports that neurons in AD start dying because they break the first law of human neuronal safety ⎯ stay out of the cell cycle.
Most normal adult neurons are permanently postmitotic; that is, they have finished dividing and are locked out of the cell cycle. In contrast, AD neurons frequently re-enter the cell cycle but fail to complete mitosis, and ultimately die. By considering this novel perspective on AD as a problem of the cell cycle, Dr. Bloom and colleagues at UVA and at the University of Alabama, Birmingham, have discovered what they call an “ironic pathway” to neuronal cell death. The process requires the coordinated action of both Aβ and tau, which are the building blocks of plaques and tangles, respectively. Dr. Bloom’s results show just how toxic the two proteins can be even when free in solution and not aggregated into plaques and tangles.
Using mouse neurons grown in culture, the UVA researchers found that Aβ oligomers, which are small aggregates of just a few Aβ molecules each, induce the neurons to re-enter the cell cycle. Interestingly, the neurons must make and accumulate tau in order for this cell cycle re-entry to occur. The mechanism for this misplaced re-entry into the cell cycle requires that Aβ oligomers activate multiple protein kinase enzymes, each of which must then attach a phosphate to a specific site on the tau protein.
Following up on the cell culture results, Dr. Bloom and colleagues confirmed that Aβ-induced, tau-dependent cell cycle re-entry occurs in the brains of mice that were genetically engineered to mimic brains with human AD. The mouse brains were found to accumulate massive numbers of neurons that had transitioned from a permanent cell cycle stop, known as G0 (G zero), to G1, the first stage of the cell cycle, by the time they were 6 months old. Remarkably, otherwise identical mice that lacked functional tau genes showed no sign of cell cycle re-entry, confirming the cell culture results.
Neuronal cell cycle re-entry, a key step in the development of AD, can therefore be caused by signaling from Aβ through tau. Thus, Aβ and tau co-conspire to trigger seminal events in AD pathogenesis independently of their incorporation into plaques and tangles. Most important, Dr. Bloom believes that the activated protein kinases and phosphorylated forms of tau identified in this study represent potential targets for early diagnosis and treatment of AD.
(Source: eurekalert.org)
Researchers at Johns Hopkins Medicine in November surgically implanted a pacemaker-like device into the brain of a patient in the early stages of Alzheimer’s disease, the first such operation in the United States. The device, which provides deep brain stimulation and has been used in thousands of people with Parkinson’s disease, is seen as a possible means of boosting memory and reversing cognitive decline.
The surgery is part of a federally funded, multicenter clinical trial marking a new direction in clinical research designed to slow or halt the ravages of the disease, which slowly robs its mostly elderly victims of a lifetime of memories and the ability to perform the simplest of daily tasks, researchers at Johns Hopkins say. Instead of focusing on drug treatments, many of which have failed in recent clinical trials, the research focuses on the use of the low-voltage electrical charges delivered directly to the brain. There is no cure for Alzheimer’s disease.
As part of a preliminary safety study in 2010, the devices were implanted in six Alzheimer’s disease patients in Canada. Researchers found that patients with mild forms of the disorder showed sustained increases in glucose metabolism, an indicator of neuronal activity, over a 13-month period. Most Alzheimer’s disease patients show decreases in glucose metabolism over the same period.
The first U.S. patient in the new trial underwent surgery at The Johns Hopkins Hospital, and a second patient is scheduled for the same procedure in December. The surgeries at Johns Hopkins are being performed by neurosurgeon William S. Anderson, M.D.
The surgery involves drilling holes into the skull to implant wires into the fornix on either side of the brain. The fornix is a brain pathway instrumental in bringing information to the hippocampus, the portion of the brain where learning begins and memories are made, and where the earliest symptoms of Alzheimer’s appear to arise. The wires are attached to a pacemaker-like device, the “stimulator,” which generates tiny electrical impulses into the brain 130 times a second. The patients don’t feel the current, says Paul B. Rosenberg, M.D., an associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine, and site director of the trial’s Johns Hopkins location.
Study in mice suggests sleep problems may be early sign of Alzheimer’s
September 5, 2012 by Michael C. Purdy
Sleep disruptions may be among the earliest indicators of Alzheimer’s disease, scientists at Washington University School of Medicine in St. Louis report Sept. 5 in Science Translational Medicine.
Working in a mouse model, the researchers found that when the first signs of Alzheimer’s plaques appear in the brain, the normal sleep-wake cycle is significantly disrupted.
“If sleep abnormalities begin this early in the course of human Alzheimer’s disease, those changes could provide us with an easily detectable sign of pathology,” says senior author David M. Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of Washington University’s Department of Neurology. “As we start to treat Alzheimer’s patients before the onset of dementia, the presence or absence of sleep problems may be a rapid indicator of whether the new treatments are succeeding.”
Holtzman’s laboratory was among the first to link sleep problems and Alzheimer’s through studies of sleep in mice genetically altered to develop Alzheimer’s plaques as they age. In a study published in 2009, he showed that brain levels of a primary ingredient of the plaques naturally rise when healthy young mice are awake and drop after they go to sleep. Depriving the mice of sleep disrupted this cycle and accelerated the development of brain plaques.
A similar rising and falling of the plaque component, a protein called amyloid beta, was later detected in the cerebrospinal fluid of healthy humans studied by co-author Randall Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology at Washington University.
The new research, led by Jee Hoon Roh, MD, PhD, a neurologist and postdoctoral fellow in Holtzman’s laboratory, shows that when the first indicators of brain plaques appear, the natural fluctuations in amyloid beta levels stop in both mice and humans.
“We suspect that the plaques are pulling in amyloid beta, removing it from the processes that would normally clear it from the brain,” Holtzman says.
Mice are nocturnal animals and normally sleep for 40 minutes during every hour of daylight, but when Alzheimer’s plaques began forming in their brains, their average sleep times dropped to 30 minutes per hour.
To confirm that amyloid beta was directly linked to the changes in sleep, researchers gave a vaccine against amyloid beta to a new group of mice with the same genetic modifications. As these mice grew older, they did not develop brain plaques. Their sleeping patterns remained normal and amyloid beta levels in the brain continued to rise and fall regularly.
Scientists now are evaluating whether sleep problems occur in patients who have markers of Alzheimer’s disease, such as plaques in the brain, but have not yet developed memory or other cognitive problems.
“If these sleep problems exist, we don’t yet know exactly what form they take—reduced sleep overall or trouble staying asleep or something else entirely,” Holtzman says. “But we’re working to find out.”
(Source: news.wustl.edu)