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New & Now: Fall 2007

Infectious Affection

Weathering the Storm

Petite Performer

Unlikely Presence

Into the Blue

Frog Friendly

The Ion Channel

Plaques and Tangles

Closer Look

 

NEURODEGENERATION: Just over 100 years ago, Alois Alzheimer described the mind-killing malady that now bears his name. Today’s scientists are getting closer to unraveling its cause.

Plaques and Tangles

After a Century of Research, Scientists Close In on the Causes of Alzheimer's

Just over a century ago, Auguste D., a 51-year-old woman from Frankfort, Germany, was locked up in the city's mental asylum. She was only intermittently able to think or speak coherently, her family told authorities. She feared her husband was cheating on her, but couldn't remember her husband's name. She knew her home was located in Frankfort, but couldn't recall the street. She had no idea what year it was. Her 37-year-old attending physician, Alois Alzheimer, often encountered her sitting on her bed with "a helpless expression."

"At lunch she eats cauliflower and pork," he observed on Nov. 26, 1901. "Asked what she is eating she answers spinach. When she was chewing meat and asked what she was doing, she answered potatoes and then horseradish. When objects are shown to her, she does not remember after a short time which objects have been shown. In between she always speaks about twins."

As her condition gradually worsened, Auguste D. began suffering from increasingly severe delusions, auditory hallucinations, aggression and paranoia. After four-and-a-half years in the asylum, she died.

Alzheimer, by now working under renowned psychiatrist Emil Kraepelin at the University of Munich, had never lost interest in the case. When he learned of Auguste D.'s death, he ordered her brain shipped to him. The autopsy showed a cerebral cortex rife with unusual clumps of plaque and neurofibrillary tangles, abnormalities that convinced Alzheimer this was no ordinary case of "senile dementia." Yet when he presented his findings at a conference in 1906, scientists in attendance seemed uninterested. Not so Kraepelin. He dubbed the condition "Alzheimer's disease," and was steadfast in his assertion that the condition represented a unique, previously unidentified disorder.

Today the shortened eponym, Alzheimer's, is universally accepted as the term identifying the mind-destroying scourge that affects millions of mostly elderly patients -- 4 million in the United States alone, according to the CDC. Meanwhile the hunt to understand the disease's terrible pathogenesis goes on.

Grace Sun and Gary Weisman, both professors of biochemistry at MU, believe the key lies in a better understanding of those curious plaque clumps. Alzheimer dubbed them "miliary foci," a name later changed to "senile plaques." Scientists now know these clumps contain fibrous aggregations of amyloid-beta, or A-beta, proteins.

Sun and Weisman, working with funding from the National Institutes of Health, have spent the past five years investigating how A-beta "misfoldings and aggregations" contribute to the plaques that debilitate patients like Auguste D. "When the A-beta is folded into an abnormal shape, it can become toxic to cells," Sun says. "While we know this has some effect on brain function, we don't know how toxic it is or at what stage the toxicity begins."

Sun and Weisman are sure of this much: Abnormal A-beta can impair the synaptic connections that occur among neurons. Because these synapses control communication among the brain cells, they affect how memory is processed. Besides neurons, A-beta also attacks astrocyte cells, which provide nutrients to neurons, and microglia, immune cells in the central nervous system. Sun and Weisman say attacks on these cells could create abnormal inflammatory responses.

The pair, along with pharmacology professor Gibson Wood of the University of Minnesota, recently received $6 million to continue their investigations. "In the past five years," Sun says, "we have started to understand how this disease works. With the new grant, we will be able to go forward to test novel hypotheses and see if there are treatments that can modify the cellular response in the brain."

The study will involve three projects. Sun will investigate the relationship between A-beta proteins and phospholipases, a group of enzymes that, when activated, destroy membranes in brain cells. Current evidence suggests that A-beta activates some of these enzymes.

Weisman will examine A-beta's role in creating inflammatory responses. Previous research has shown that a new type of receptors controls the enzyme that produces A-beta proteins and regulates inflammation. Finding a way to suppress the receptors' function, therefore, could lead to new treatments that would minimize both A-beta production and brain inflammation.

Wood will focus on cholesterol, molecules highly enriched in brain membranes. His previous research has shown statins, drugs designed to suppress cholesterol synthesis, may decrease oxidative stress and inhibit the cell death process. His new study will determine whether statins might also combat the ill effects of A-beta.

Findings from the research program have thus far been published in the Journal of Neuroinflammation, the Journal of Neuroscience and the Journal of Biological Chemistry. In addition to NIH funding, support for the study has been provided by MU research matching funds.

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Published by the Office of Research.

©2009 Curators of the University of Missouri. Click here to contact the editor.

 

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