Northwestern Neuroscientists Report Findings In Studies on Alzheimer's Disease

November 16, 1996

WASHINGTON, D.C. --- Research findings on Alzheimer's disease, stress and depression, alcoholism and addiction will be reported by scientists from Northwestern University at the Neuroscience Society annual conference in Washington, D.C. Other presentations by Northwestern researchers will cover a variety of projects on the cerebrocortex, genes and biorhythms, as well as reconstruction of neurocircuitry and motor, cellular and systems neuroscience. The researchers will present their studies at the conference, being held Nov. 16-21 at the Washington Convention Center.

Highlights of some of their presentations include:
Alzheimer's Disease
Stress and Depression
Reconstruction of Neurocircuitry
Biorhythm Regulation
Cellular Neuroscience

--Increased enzyme activity may signal development of Alzheimer's dementia. The plaques and tangles in the brain of patients with Alzheimer's disease show intense activity of butyrylcholinesterase (BChE), an enzyme that in normal brains is present in extremely low quantities and in only a small number of neurons and glia cells. M.-Marsel Mesulam, M.D., director of behavioral and cognitive neurology and the Alzheimer's disease program at the Medical School, and his colleagues at Northwestern and Harvard University have found that BChE activity increases at the intermediate stage of plaque formation and that it may therefore be a factor in the transformation of benign protein deposits in the brain into the plaques associated with the nerve degeneration and dementia of Alzheimer's disease.

--S100 Beta in Alzheimer's disease--Too much of a good thing? S100 beta, a protein expressed by astrocyte cells in the brain, plays an important role in the growth and maintenance of the nervous system. However, researchers believe that high concentrations of S100 beta also may be involved in the development of Alzheimer's disease. Linda Van Eldik, professor of cell and molecular biology, and co-investigators at Northwestern recently showed that long-term exposure of astrocytes to high concentrations of S100 beta stimulated production of nitric oxide and caused a toxic response or even cell death. They also found that the cell death induced by addition of S100 beta correlated with the levels of nitric oxide production.

Regulator of "stress hormone" production found. Chronic stress produces a number of effects on the brain and the endocrine and immune systems, with a wide variety of consequences, including psychiatric illness and increased vulnerability to infections. ACTH, better known as corticotropin hormone, is the major regulator of the body's adaptive response to stress. For some time, scientists have postulated the existence of a substance that inhibits ACTH synthesis and secretion. Now, a group of researchers from Northwestern University Medical School and the University of Pennsylvania, Philadelphia, have identified a peptide, named prepro-thyrotropin-releasing hormone (TRH) 178-199, that inhibits and stimulates ACTH production and secretion in vitro and stress-induced ACTH secretion in vivo. According to Eva Redei, associate professor and behavioral sciences and the Ruth and Evelyn Dunbar Scholar at Northwestern, "The clinical significance of this probable coordinated regulation of ACTH and thyrotopin secretion is apparent from the frequency of thyroid and adrenal abnormalities, particular in depression." Redei said their results may have important implications on the treatment of number of psychiatric and autoimmune disorders.

--Striking new biochemical evidence shows a link between alcoholism and nicotine addiction. A study by pharmacologists at Northwestern may explain the high correlation between alcoholism and smoking. Although about 10 percent of the population are heavy smokers, other research shows that among alcoholics, 70 to 90 percent are heavy smokers.

Alcoholic beverages modify the activity of a neuronal nicotinic receptor -- the same target site in the nervous system that is altered by exposure to the nicotine in tobacco. Nicotine stimulates and then desensitizes the neuronal nicotinic acetylcholine receptor, according to Toshio Narahashi, the John Evans Professor of Molecular Pharmacology and Biological Chemistry and the Alfred Newton Richards Professor, who headed the study.

"The acetylcholine receptor of the nicotine addict may be slightly desensitized, meaning that higher doses of alcohol are required to stimulate it," he said.

Narahashi and colleagues also found that alcohol affects the acetylcholine receptors at minute concentrations -- much lower than those reported for its other target sites in the nervous system. This suggests that these receptors may be important target sites of alcohol, particularly in the early stages of alcohol intoxication.

--Neurons from transplanted olfactory bulb integrate into host neurons. Enrico Mugnaini, M.D., the Edgar F. Stuntz Professor and director of the Northwestern University Institute for Neuroscience (NUIN), in collaboration with investigators from Hungary and Germany, successfully transplanted and integrated relay neurons from the olfactory bulb of a transgenic mouse embryo into a host mouse whose olfactory bulb had been surgically removed.

When olfactory bulbs are removed surgically, the ability to discriminate odors is lost.

After two months, the transplant developed into a bulb-like structure. Mugnaini said that the grafted neurons showed long-term survival, received afferent synapses from regenerated host olfactory terminals within a newly formed network of nerve cells and extended their axons onto dendrites of host neurons.

Results of this study indicate the possibility that olfactory bulb function may be restored in the host following transplantation. Mugnaini said that more research is required to determine application of these findings in humans who have lost their sense of smell.

--Melatonin, the hormone of darkness, may help regulate blood flow in brain. Melatonin, the hormone that plays a vital role in setting the body's biological clock, has received widespread attention for its use in jet lag and sleep and seasonal affective disorders. Melatonin stimulates specific proteins, called receptors, on the surface of certain cells in the brain and in the body. Now, Margarita Dubocovich, professor of molecular pharmacology and biological chemistry, and other scientists at Northwestern University, the University of California, Irvine, and the University of Lund, Sweden, have found functional melatonin (ML1A) receptors in the cerebral and peripheral arteries in both an animal model and in humans.

Their studies suggest that melatonin regulates the cerebral circulation in humans and other mammals via vascular ML1A receptors. Dubocovich said that activation of these receptors may contribute to circadian variations in cerebral blood flow and onset of stroke, as well as to possible side effects of melatonin administration for sleep disorders.

--New brain cell with chemical "mousetrap" discovered by Northwestern neuroscientists. A unique neuron known as a unipolar brush cell (UBC) was recently discovered in the mammalian cerebellum. Named by NUIN director Enrico Mugnaini, M.D., the UBC has several unusual features, including the largest synapse ever found in the brain.

N. Traverse Slater, professor of physiology at Northwestern, believes the synapse's size enables it to "trap" neurotransmitters (in this case, chemical "messengers") after release, resulting in a prolonged discharge from the UBC.

Slater explained that, at most synapses, neurotransmitter molecules escape very rapidly following release -- within a few hundredths of a second. But the chemical "mousetrap" in the UBC holds on to the neurotransmitter for as long as 5 seconds.

Even more interesting, Slater said, is that UBCs are found only in mammals, and the highest numbers are seen in the human brain.

Also contributing to the research on UBCs were Northwestern University Medical School researchers R. Anelli; Lester I. Binder, associate professor of cell and molecular biology; Shane Cunha; Maria R. Dino; Ronald E. Kettner, research assistant professor of physiology; Gregory A. Kinney; Linda S. Overstreet; and Gabriella Sekerkova.

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