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