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

Abstract

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

Large-scale proteomic analysis of human prefrontal cortex identifies proteins associated with cognitive trajectory in advanced age

“…Myelin basic protein, MBP, can influence beta-amyloid accumulation in the brain. Indeed, deletion of MBP gene led to a significant reduction in cerebral beta-amyloid levels in Tg-3xFAD mice 64 , consistent with our finding of decreased abundance of MBP being associated with cognitive stability.…”

In-vivo imaging of grey and white matter neuroinflammation in Alzheimer’s disease: a positron emission tomography study with a novel radioligand, [18F]-FEPPA

“…60 A study in a transgenic mouse model of AD indicated that elevated microglia activation in the white matter might be associated with the absence of myelin basic protein. 61 Although DTI studies have unequivocally showed that patients with AD have an extensive white matter microstructural damage, 22 it is yet to be determined whether these white matter changes are related to increases in neuroinflammation. Consistent with our results, several studies have reported associations between the loss of integrity of white matter microstructure as measured by DTI and cognitive impairment in patients with AD.…”

Myelin Basic Protein Associates with AβPP, Aβ1-42, and Amyloid Plaques in Cortex of Alzheimer's Disease Brain

“…Moreover, intact purified MBP can degrade Aβ protein and peptides, whereas degraded MBP lacking autolytic activity cannot degrade Aβ 40 or Aβ 42 [33]. Recently, a study in bigenic Tg-5xFAD/MBP−/− mice shows a significant decrease of insoluble Aβ and decreased parenchymal plaque deposition at an early age [61]. These studies suggest that some form of MBP is necessary for plaque formation.…”