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The Journal of Neuroscience, March 15, 1998, 18(6):2161-2173

Fibrillar -Amyloid Induces Microglial Phagocytosis, Expression of Inducible Nitric Oxide Synthase, and Loss of a Select Population of Neurons in the Rat CNS In Vivo

Derik T. Weldon¹, Scott D. Rogers², Joseph R. Ghilardi², Matthew P. Finke², James P. Cleary^{3, 5}, Eugene O'Hare^{4, 5}, William P. Esler⁶, John E. Maggio⁶, and Patrick W. Mantyh²

¹ School of Medicine, Departments of ² Preventive Sciences, ³ Psychology, and ⁴ Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455, ⁵ Geriatric Research Education and Clinical Center, Veterans Affairs Medical Center, Minneapolis, Minnesota 55417, and ⁶ Department of Pharmacology and Cell Biophysics, University of Cincinnati, Cincinnati, Ohio 45267

To determine the stability of -amyloid peptide (A) and the glial and neuronal changes induced by A in the CNS in vivo, we made single injections of fibrillar A (fA), soluble A (sA), or vehicle into the rat striatum. Injected fA is stable in vivo for at least 30 d after injection, whereas sA is primarily cleared within 1 d. After injection of fA, microglia phagocytize fA aggregates, whereas nearby astrocytes form a virtual wall between fA-containing microglia and the surrounding neuropil. Similar glial changes are not observed after sA injection. Microglia and astrocytes near the injected fA show a significant increase in inducible nitric oxide synthase (iNOS) expression compared with that seen with sA or vehicle injection. Injection of fA but not sA or vehicle induces a significant loss of parvalbumin- and neuronal nitric oxide synthase-immunoreactive neurons, whereas the number of calbindin-immunoreactive neurons remains unchanged. These data demonstrate that fA is remarkably stable in the CNS in vivo and suggest that fA neurotoxicity is mediated in large part by factors released from activated microglia and astrocytes, as opposed to direct interaction between A fibrils and neurons.

Key words: Alzheimer's disease; glia; microglia; astrocyte; neurotoxicity; nitric oxide synthase; inducible nitric oxide synthase

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Copyright © 1998 Society for Neuroscience  0270-6474/98/1862161-13$05.00/0

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