Alzheimer’s disease (AD) is a tragic disease that robs an individual of their memory and mental capacity. One in eight people over the age of 65 now suffer from the disease and one in two people over 85 are diagnosed with the disease. Contrary to popular belief, Alzheimer’s does not only affect the elderly. Familial Alzheimer’s disease (FAD), an offshoot of the disease, affects those as young as 30.
The Study
Alzheimer’s is a complex disease, and so too are the attempts to explain it. One way to understand how the brain works to cause the disorder is by using computational modeling, (a series of equations) to characterize an individual aspect that is important to the disease. Biomedical engineers Lydia S. Glaw and Thomas C. Skalak, Ph.D., of the Department of Biomedical Engineering, University of Virginia, Charlottesville, have created a model to examine the role of certain proteins in the development of the disease.
Their findings are contained in the study entitled "A Computational Model of the Role of Presenilin-1 and Glycogen Synthase Kinase-3 in Familial Alzheimer’s Disease." They will present their findings at the 122nd Annual Meeting of the American Physiological Society, which is part of the Experimental Biology 2009 scientific conference. The meeting will be held April 18-22, 2009 in New Orleans.
The researchers constructed a simple computational model to measure plaques and tangles and their influence in causing FAD. The model tested the hypothesis that certain variables—genetic mutations in proteins and “tau” tangles—might be predicative of the development of the disease. The main hypothesis that the model tested was the idea that GSK3 is a link between amyloid beta buildup and tau tangle development.
Brain Plaque: A Major Instigator?
The proteins presenilin-1 (PS1) (a mutated gene found in familial AD) and glycogen synthase kinase (GSK-3) (a protein) and amyloid beta (Aβ) plaque (amino acids that are found in large quantity in AD) were studied to quantitatively examine their roles in the development of Alzheimer’s pathology. The elements (in the form of existing research data) were applied to the model, which was constructed of kinetic equations developed from literature searches, and analyzed the interactions of the proteins and complexes under various scenarios. The model is a first-of-its-kind approach to modeling, understanding and predicting Alzheimer’s pathways.
Results: No Link Between A Protein and Plaques, Tangles
GSK3 had a large effect on tangle formation, but very little on the plaques. Activating GSK3 was not found to be sufficient to cause changes in the brain to the extent seen in Alzheimer’s patients. However, overproduction of GSK3 as opposed to activation may be able to cause those changes. Nor was there any link found between amyloid beta plaque and tau tangles. The main conclusion of the model so far is that no single change to the system can cause Alzheimer’s disease. Multiple changes, such as a PS1 mutation combined with GSK3 over-activation can, however. A multi-pronged approach to treating the disease may be best.
Conclusion
Glaw’s model can be used for additional pathway analysis. She views modeling as a useful way for better understanding this complex, multi-layered disease.
Computational Model Examines The Pathways Of Alzheimer's That Strikes At The Young
Alzheimer's Disease: Are Plaques and Tangles a Symptom, Not the Cause?
Karl Herrup thinks that the national research effort to understand Alzheimer's disease has gone about as far as it can go with its current theories. And that's not far enough. Alzheimer's disease is an incurable, degenerative, eventually fatal disease that attacks cognitive function. It affects more than 26 million people around the world and is the most common form of dementia among people over the age of 65. Over the last three decades, most Alzheimer's research has been governed by the "amyloid cascade hypothesis."
The theory -- which holds that the beta-amyloid peptide is the key to the initiation and progression of the disease -- has had significant appeal as the peptide is the main ingredient of the disease-related plaques that are common in the brains of those affected.
Indeed, this persistent correlation has led researchers to spend many years and many millions of dollars looking for ways to prevent plaques as a way of treating, curing or preventing Alzheimer's. In recent years, however, dozens of human clinical trials based on this theory have failed.
Herrup, the chair of the Department of Cell Biology and Neuroscience at Rutgers University, suggests an alternative perspective, which he has set forth in a paper published December 14 in the Journal of Neuroscience. Pointing out that age is the most important risk factor in the disease, he suggests a new hypothesis with age as the starting point.
Age slows the brain's agility and blunts its responses to change; on their own, however, age-related changes lead only to a slow 'natural' decline in cognitive function, Herrup says. He posits that while these changes might increase one's risk of the Alzheimer's, they do not cause the disease.
Herrup believes three three key steps that are needed for an individual to progress from this natural path to the full spectrum of Alzheimer's clinical symptoms: an initiating injury that is probably vascular in nature; an inflammatory response that is both chronic and unique to Alzheimer's; and a cellular change of state, a one-way cell biological door that permanently alters the physiology of neurons and several other cell types in the Alzheimer's disease brain.
"The initiating injury might trigger a protective response in the brain cells," Herrup said. "But the real problem is that in the elderly the response doesn't know when to quit. It continues even after the injury itself subsides. In the end, the real damage is done by the persistence of the response and not by the injury, itself."
Herrup hopes his new theory will stimulate discussion and open the way to new experimental and diagnostic advances. "This new hypothesis, for example, emphasizes the value of anti-inflammatory approaches to the prevention of Alzheimer's disease," Herrup says.
He concedes that the individual components of the model aren't entirely new, but points out that by rearranging their order and shifting their priority, his view has enormous implications for modern Alzheimer's research.
"My hypothesis implies that beta-amyloid aggregation is not a central part of the biology of Alzheimer's disease," Herrup says. "It predicts that one can have plaques without having Alzheimer's and that one can have Alzheimer's without having plaques.
"Researchers should be cautious about following up these predictions, but since we've gone about as far as we can with our current hypothesis, we may have reached a point where too much caution is ill-advised. It's time to re-imagine Alzheimer's disease, so we can think creatively about treating it."
Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment.
Anti-Inflammatory Drug Blocks Brain Plaques
An anti-inflammatory drug may help restore brain function in patients with Alzheimer's disease, according to an animal study recently published in the Journal of Experimental Medicine.
Brain destruction in Alzheimer's disease is caused by the build-up of a protein called amyloid beta in the brain, which triggers damaging inflammation and the destruction of nerve cells. Scientists had previously shown that preventing individual amyloid beta proteins from sticking to one another minimized brain lesions and protected nerve cells against damage.
The new study--a collaborative effort by researchers in Germany and the US--shows that an anti-inflammatory drug (called CNI-1493) may have the same effect. The drug--already tested in humans for the treatment of inflammatory diseases--protected nerve cells against amyloid beta --induced damage in culture. In mice prone to developing an Alzheimer's-like disease, the drug decreased brain inflammation and improved memory and cognitive function.
Other anti-inflammatory drugs, such as ibuprofen, have been shown to reduce Alzheimer's disease lesions in the brains of rodents, but CNI-1493 appears to be faster and more effective. If these results hold up in humans, CNI-1493 may provide a more effective alternative to current Alzheimer's therapies, which temporarily prolong the function of nerve cells but do not prevent their destruction.
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