FIBRILLAR BETA-AMYLOID INDUCES MICROGLIAL PHAGOCYTOSIS, EXPRESSION OFINDUCIBLE NITRIC-OXIDE SYNTHASE, AND LOSS OF A SELECT POPULATION OF NEURONS IN THE RAT CNS IN-VIVO

To determine the stability of beta-amyloid peptide (A beta) and the gl ial and neuronal changes induced by A beta in the CNS in vivo, we made single injections of fibrillar A beta (fA beta), soluble A beta (sA b eta), or vehicle into the rat striatum. Injected fA beta is stable in vivo for at least 30 d after injection, whereas sA beta is primarily c leared within 1 d. After injection of fA beta, microglia phagocytize f A beta aggregates, whereas nearby astrocytes form a virtual wall betwe en fA beta-containing microglia and the surrounding neuropil. Similar glial changes are not observed after sA beta injection. Microglia and astrocytes near the injected FA beta show a significant increase in in ducible nitric oxide synthase (iNOS) expression compared with that see n with sA beta or vehicle injection. Injection of fA beta but not sA b eta or vehicle induces a significant loss of parvalbumin- and neuronal nitric oxide synthase-immunoreactive neurons, whereas the number of c albindin-immunoreactive neurons remains unchanged. These data demonstr ate that fA beta is remarkably stable in the CNS in vivo and suggest t hat fA beta neurotoxicity is mediated in large part by factors release d from activated microglia and astrocytes, as opposed to direct intera ction between A beta fibrils and neurons.