Human Brain Microtubule Assembly in Aging and Alzheimer's Disease
Principal Investigator
Dennis Sparkman, PhD
The University of Texas Southwestern Medical Cente
Ennis, TX, USA
About the Research Project
Program
Award Type
Standard
Award Amount
$142,584
Active Dates
April 01, 1990 - March 31, 1992
Grant ID
A1990066
Summary
Microtubules are long tube-like structures that serve to give nerve cells their shape and to transport substances to the nerve terminals. They are made up of a protein called tubulin, but their assembly is promoted by a group of proteins called the microtubule-associated proteins. These tubules give the cell it ‘ s shape by forming a scaffolding for support, and can move substances within the long network of nerve cell processes by assembling the tubules at one end while disassembling it at the other. This gives a sort of conveyer belt effect. Brain tissue is a very rich source of microtubules. Microtubules can be isolated from brain tissue and assembled in a test tube. All that is necessary is an energy source such as GTP, and a drug called taxol, which stabilizes the microtubules.
It has been reported t hat microtubules cannot be assembled from the soluble portion of Alzheimer brain. Our work has shown that this does appear to be the case in some Alzheimer brains, but we have been able to assemble abundant microtubules from others Other work that we have done on microtubules in the human brain involves the cerebellum, or the back portion of the brain. We have studied 13 brains from humans who had normal brain function when they died. Microtubules were isolated and measured in triplicate experiments, and when analyzed statistically, it was found that the most important factor in determining the final yield was the time that elapsed after death. Age of the individual was also a factor in determining yield, in that the older the individual, the shorter the time that could elapse after death before microtubules could no longer be assembled. This would lead us to speculate that the failure of microtubules from some Alzheimer brains to assemble may only be related to the age of the patient and time since death. However, in some Alzheimer brains, there does appear to be a reduced amount of microtubules that can assemble for the age and time since death. In order to be able to understand such possible defects in microtubule assembly in Alzheimer brains, it is necessary to determine the optimal amount of microtubules that can be obtained from a normal brain for any particular age and at any time interval after death. This would allow us to establish a mathematical formula that would predict the amount of microtubules that could theoretically be obtained from a particular brain. We could then predict the a mount of microtubules that should be able to be isolated from a unaffected brain region such as cerebellum in Alzheimer’s disease, and to compare these results to those from an affected area , such as the cerebral cortex. If a defect in microtubule assembly can be demonstrated in AD, such factors such as the amount of tubulin in the soluble fraction and its functional state would be examined. Finally. one of the microtubule-associated proteins, tau, has been reported to be abnormal in AD. We would also examine tau, isolated from AD brains, to determine whether it is this abnormal form that interferes with microtubule assembly in AD.
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