We examined the neurotoxicity of the 40 amino acid fragment of beta amyloid peptide (Aβ1-40) in cultured hippocampal slices. When injected into area CA3, Aβ1-40 produced widespread neuronal damage. Injection of the reverse sequence peptide, Aβ40-1, or vehicle alone produced little damage. The distribution Aβ1-40 was highly correlated with the area of neuronal damage. Thioflavine S and electron microscopic analysis confirmed that injected Aβ1-40 formed 7-9 nm AD type amyloid fibrils in the cultures. Aβ1-40 also altered the number of GFAP immunoreactive astrocytes and ED-1 immunoreactive microglia/macrophages within and around the Aβ1-40 deposit. The observed neurotoxicity of Aβ1-40 in hippocampal slice cultures provides evidence that this peptide may be responsible for the neurodegeneration observed in AD. © 1995.