DIMENSIONS Winter 1997

SPOTLIGHT ON RESEARCH: ADRC PILOT STUDIES PAVE PATH TO FUTURE RESEARCH

A major goal of the Alzheimer's Disease Research Center (ADRC) is to encourage applied and basic research on AD and related disorders. To help investigators begin new projects in Alzheimer's research, the ADRC provides grants for short-term pilot studies. Since 1995, the Center has funded the following six studies.

LOCALIZATION OF FE65 GENE EXPRESSION IN THE MURINE CNS

Working with an animal model, Dr. Steven Bressler, research assistant professor of pathology, and his colleagues are investigating a gene that may be involved in Alzheimer's disease. Genes direct production of proteins‹components of all living cells that carry out a wide variety of functions in the body.

The researchers have isolated a protein called Fe65 that is found in the hippocampus and other areas of brain directly affected by AD. Their work has shown that Fe65 strongly interacts with amyloid precursor protein (APP), another brain protein that is a major focus of AD research. Through a series of poorly understood reactions, APP is broken down leaving beta amyloid, a major component of the plaques found in large numbers in the brains of people with AD.

As well as documenting the presence of Fe65, Bressler and his colleagues have been investigating the function of Fe65 and have evidence that suggests it is involved in signal transduction-a process by which messages from outside the cell are communicated to the inside resulting in certain genes being turned on and certain genes being turned off. Learning more about the link between Fe65 and APP could be an important step in understanding the mechanism that causes the degeneration of brain cells in AD.

POSSIBLE MODULATION OF GLUCOCEREBROSIDASE ACTIVITY AND THE PHENOTYPE OF GAUCHER DISEASE BY A NEWLY IDENTIFIED GENE

A study led by Dr. Paul Bornstein, professor of biochemistry, investigated a possible relationship between genetic factors related to the dementia that is a symptom of one form of Gaucher disease and the dementia of AD. The study was prompted by identification of a new gene closely linked to the GC gene, whose mutation causes Gaucher disease. The researchers examined the hypothesis that the enzyme produced by the newly identified gene could influence activity of the GC gene and be related to the particular form of Gaucher disease marked by dementia. Results of the study indicate that the enzyme is not related to the defect that causes Gaucher disease, but instead functions in the mitochondria‹structures within cells that help to provide energy for cellular activity.

NEUROTOXIC NEUROTROPHIN RECEPTORS

Within a cell, a protein that responds to a signal from a specific chemical in the body is known as a receptor. Receptors respond to chemical signals by starting or stopping particular activities within the cell. Each brain cell has many different receptors and each receptor is activated by a distinct type of chemical.

Previous studies have suggested that a certain receptor called p75, which is activated by a type of chemical known as nerve growth factor, is involved in the degeneration of brain cells in Alzheimer's disease. Based on this evidence, Dr. Mark Bothwell, professor of physiology and biophysics, is investigating p75 receptors and their relationship to cell death.

Results of Bothwell's pilot study, which produced evidence that p75 receptors directly trigger cell death, hold promise for future research that may ultimately shed light on how to prevent the death of brain cells in AD.

THE AMYLOID PRECURSOR PROTEIN AS A SYNAPTIC ECM RECEPTOR

A protein fragment known as beta amyloid is a major component of the plaques that clog the brain in Alzheimer's disease. Beta amyloid is a product of the breakdown of a larger molecule called amyloid precursor protein (APP). The cause of this breakdown is unknown.

The goal of a study conducted by Dr. Steven Carlson, associate professor of physiology and biophysics, was to learn more about the formation of beta amyloid by determining APP's normal function in the brain. Evidence suggests that the normal role of APP might be to act as an extracellular matrix receptor on one side of a synapse‹the junction between two nerve cells where one cell communicates with the next by releasing a chemical messenger that crosses the gap and activates the cell on the other side. Such a receptor would help hold the synapse together by binding with a protein in the extracellular matrix.

Carlson's work has confirmed that APP is present on the ends of nerve cells, a finding that is consistent with the hypothesis that APP functions as an extracellular matrix receptor. Further research is required to determine what protein of the extracellular matrix binds with APP.

BEHAVIORAL TREATMENT OF SLEEP PROBLEMS IN DEMENTIA CAREGIVERS

Getting enough sleep can be difficult for caregivers of patients with dementia. Dr. Sue McCurry, assistant professor of psychiatry and behavioral sciences, conducted a study to determine if caregivers' sleep could be improved.

McCurry measured outcomes of a four-week program teaching sleep improvement techniques in 36 healthy older dementia caregivers. Subjects in the active treatment reported improvement in sleep latency (the length of time it takes to fall asleep), sleep efficiency (the amount of time spent sleeping compared with the amount of time spent in bed) and in sleep quality. Caregivers' sleep improved even though there was no change in the number of times patients woke at night. The behavioral techniques caregivers had learned enabled them to go back to sleep more easily and sleep more soundly once they had dealt with the patient.

Although subjects stayed in the study once they were recruited, McCurry had difficulty getting the number of subjects she hoped for. She speculates that recruiting problems may have been related to the reluctance many caregivers feel to add an activity to their already burdened lives that is not directly related to patient care.

REGULATION OF CHOLINERGIC RECEPTOR EXPRESSION IN CEREBRAL CORTICAL NEURONS

Drugs for treating symptoms of the cognitive decline of AD, such as Aricept (see article this issue), work on the principle of increasing activity in the cholinergic system of the brain. Cholinergic activity has two aspects, production of the neurotransmitter acetylcholine, which is a chemical messenger made by nerve cells, and receipt of the message at a site, known as a receptor, on the targeted cell. Currently available drugs increase the amount of acetylcholine available to transmit messages. Another strategy that may someday increase cholinergic activity and alleviate AD symptoms would be to increase the response of acetylcholine receptors.

A study led by Dr. Thomas Reh, professor of biological structure, is investigating a recently discovered family of proteins, called neuregulins, that are known to regulate the response of acetylcholine receptors at sites where nerve cells send messages to muscle cells. Using an animal model, Reh is seeking to determine if increasing neuregulins in the brain can enhance the response of acetylcholine receptors in the brain's nerve cells. Results of this research may ultimately provide another direction for developing effective drug therapies for AD.


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