Cerebral amyloid-β (Aβ) deposition is central to the neuropathological definition of Alzheimer disease (AD) with Aβ related toxicity being linked to its β-sheet conformation and/or aggregation. We show that a β-sheet breaker peptide (iAβ5) dose-dependently and reproducibly induced in vivo disassembly of fibrillar amyloid deposits, with control peptides having no effect. The iAβ5-induced disassembly prevented and/or reversed neuronal shrinkage caused by Aβ and reduced the extent of interleukin-1β positive microglia-like cells that surround the Aβ deposits. These findings suggest that β-sheet breakers, such as iAβ5 or similar peptidomimetic compounds, may be useful for reducing the size and/or number of cerebral amyloid plaques in AD, and subsequently diminishing Aβ-related histopathology.