The absence of myelin basic protein promotes neuroinflammation and reduces amyloid β-protein accumulation in Tg-5xFAD mice

Background: Abnormal accumulation of amyloid beta-protein (A beta) in the brain plays an important role in the pathogenesis \of Alzheimer's disease (AD). A beta monomers assemble into oligomers and fibrils that promote neuronal dysfunction. This assembly pathway is influenced by naturally occurring brain molecules, the A beta chaperone proteins, which bind to A beta and modulate its aggregation. Myelin basic protein (MBP) was previously identified as a novel A beta chaperone protein and a potent inhibitor for A beta fibril assembly in vitro. Methods: In this study, we determined whether the absence of MBP would influence A beta pathology in vivo by breeding MBP knockout mice (MBP-/-) with Tg-5xFAD mice, a model of AD-like parenchymal A beta pathology. Results: Through biochemical and immunohistochemical experiments, we found that bigenic Tg-5xFAD/MBP-/- mice had a significant decrease of insoluble A beta and parenchymal plaque deposition at an early age. The expression of transgene encoded human A beta PP, the levels of C-terminal fragments generated during A beta production and the intracellular A beta were unaffected in the absence of MBP. Likewise, we did not find a significant difference in plasma A beta or cerebrospinal fluid A beta, 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 A beta 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 A beta deposition in transgenic mice and that this consequence may result from increased glial activation and expression of MMP-9, an A beta degrading enzyme.