Fibrillar beta -Amyloid Induces Microglial Phagocytosis, Expression of Inducible 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 (Abeta) and the glial and neuronal changes induced by Abeta in the CNS in vivo, we made single injections of fibrillar Abeta (fAbeta), soluble Abeta (sAbeta), or vehicle into the rat striatum. Injected fAbeta is stable in vivo for at least 30 d after injection, whereas sAbeta is primarily cleared within 1 d. After injection of fAbeta, microglia phagocytize fAbeta aggregates, whereas nearby astrocytes form a virtual wall between fAbeta-containing microglia and the surrounding neuropil. Similar glial changes are not observed after sAbeta injection. Microglia and astrocytes near the injected fAbeta show a significant increase in inducible nitric oxide synthase (iNOS) expression compared with that seen with sAbeta or vehicle injection. Injection of fAbeta but not sAbeta 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 fAbeta is remarkably stable in the CNS in vivo and suggest that fAbeta neurotoxicity is mediated in large part by factors released from activated microglia and astrocytes, as opposed to direct interaction between Abeta fibrils and neurons.