Immunopathology: Neurotoxic Microglia and Neuronal Death

Principal Investigators:
Dana Giulian, M.D., Ph.D.
Lanny J. Haverkamp, Ph.D.

Our laboratories are interested in the role which microglia play in the pathogenesis of Alzheimer's disease (AD). Microglia, as the principal immune element of the brain, possess an extensive arsenal of response to defend the brain against a wide assortment of external threats by secretion of a number of potentially cytotoxic substances. To summarize our published work (ref. 1), we have shown that (1) Stimulated microglia are abundant in AD brain, in association with senile plaques, (2) The senile plaque (diagnostic for AD) and plaque protein, taken from AD brain autopsy material, stimulate microglia in vitro to produce a potent neurotoxin, (3) The same neurotoxin (termed NTox ) can be extracted from AD brain, and (4) This neurotoxin, injected into rat brain, causes selective neuronal death which can be prevented by administering drugs which block the NMDA-sensitive glutamate receptor.

Senile plaques, as the defining structural abnormalities of AD, are likely to underlie pathogenesis of the disease. Neurotoxic microglia, chronically activated by plaques, may play a significant secondary role in AD pathogenesis by release of neuron poisons upon contact with neuritic or core plaques. NTox is secreted by plaque-stimulated microglia and is found in the AD brain. Taken together, these findings indicate a fundamental relationship among senile plaques, reactive glia, and the neuronal injury observed in AD, offering new directions for development of treatment strategies. Attempts to use immunosuppressive therapies in AD, now being planned or underway, require a basic understanding of reactive microgliosis in the AD brain and an appreciation of activating mechanisms and types of cytotoxins produced.
Click on picture for larger version.

(A) At low magnification, this section has been reacted in such a way to visualize activated microglia. It is apparent that there are clusters of the cells throughout the brain.

(B) at higher power magnification, the individual microglia crowding around a structure are apparent. Arrows point out individual cells.

(C) This photomicrograph is of the same area as in (B), but is viewed under epifluorescence after thioflavin staining to visualize senile plaques. As can be seen by the bright area underneath the microglia (dark shadows), it is the plaque about which the microglial cells are clustering.
Selected Reference:
1) Giulian, D., Haverkamp, L.J., Li, J., Karshin, W.L., Yu, J., Tom, D., Li, X. and Kirkpatrick, J.B. Senile plaques stimulate microglia to release a neurotoxin found in Alzheimer brain. Neurochem. Int., 27:119-137, 1995.
Department of Neurology, Baylor College of Medicine

Comments to: neurons

URL:http://www.bcm.tmc.edu/neurol/index.html