BACKGROUND: Abnormal accumulation of amyloid ß-protein (Aß) in the brain plays an important role in the pathogenesis \of Alzheimer's disease (AD). Aß monomers assemble into oligomers and fibrils that promote neuronal dysfunction. This assembly pathway is influenced by naturally occurring brain molecules, the Aß chaperone proteins, which bind to Aß and modulate its aggregation. Myelin basic protein (MBP) was previously identified as a novel Aß chaperone protein and a potent inhibitor for Aß fibril assembly in vitro. METHODS: In this study, we determined whether the absence of MBP would influence Aß pathology in vivo by breeding MBP knockout mice (MBP-/-) with Tg-5xFAD mice, a model of AD-like parenchymal Aß pathology. RESULTS: Through biochemical and immunohistochemical experiments, we found that bigenic Tg-5xFAD/MBP-/- mice had a significant decrease of insoluble Aß and parenchymal plaque deposition at an early age. The expression of transgene encoded human AßPP, the levels of C-terminal fragments generated during Aß production and the intracellular Aß were unaffected in the absence of MBP. Likewise, we did not find a significant difference in plasma Aß or cerebrospinal fluid Aß, suggesting these clearance routes were unaltered in bigenic Tg-5xFAD/MBP-/- mice. However, MBP-/- mice and bigenic Tg-5xFAD/MBP-/- mice exhibited elevated reactive astrocytes and activated microglia compared with Tg-5xFAD mice. The Aß degrading enzyme matrix metalloproteinase 9 (MMP-9), which is expressed by activated glial cells, was significantly increased in the Tg-5xFAD/MBP-/- mice. CONCLUSIONS: These findings indicate that the absence of MBP decreases Aß deposition in transgenic mice and that this consequence may result from increased glial activation and expression of MMP-9, an Aß degrading enzyme.