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.

Background: Fibrillar amyloid proteins deposit in plaques and blood vessels in the brain in Alzheimer disease and related disorders. Results: Early formation of amyloid plaques impedes subsequent amyloid accumulation in blood vessels. Conclusion: Amyloid deposition in one compartment can impact amyloid accumulation in another compartment in the brain. Significance: Learning how amyloid proteins influence further formation is important for understanding the progression of pathology in neurodegenerative diseases.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is the leading cause of dementia in the elderly. Amyloid-β protein (Aβ) depositions in both the brain parenchyma and the cerebral vasculature are recognized as important pathological components that contribute to the cognitive impairments found in individuals with AD. Because pharmacological options have been minimally effective in treating cognitive impairment to date, interest in the development of preventative lifestyle intervention strategies has increased in the field. One controversial strategy, cognitive-specific stimulation, has been studied previously in human participants and has been widely commercialized in the form of 'brain-training games.' In the present study, we developed a highly controlled, isolated cognitive training intervention program for mice. Two transgenic mouse lines, one that develops Aβ deposition largely in brain parenchyma, and another in the cerebral microvasculature, progressed through a series of domain-specific tasks for an average of 4 months. Despite the high intensity and duration of the intervention, we found little evidence of positive benefits for AD amyloid pathologies and post-training cognitive testing in these two models. Taken together, these results support the current evidence in human studies that cognitive-specific stimulation does not lead to a measurable reduction in AD pathology or an improvement in general brain health.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is characterized by extensive deposition of fibrillar amyloid β (Aβ) in the brain. Previously, myelin basic protein (MBP) was identified to be a potent inhibitor to Aβ fibril formation and this inhibitory activity was localized to the N-terminal residues 1–64, a fragment designated MBP1. Here we show that modest neuronal expression of a fusion protein of the biologically active MBP1 fragment and the enhanced green fluorescent protein (MBP1-EGFP) significantly improved the performance of spatial learning memory in Tg-5xFAD mice, a model of pathologic Aβ accumulation in brain. The levels of insoluble Aβ and fibrillar amyloid were significantly reduced in bigenic Tg-5xFAD/Tg-MBP1-EGFP mice. Quantitative stereological analysis revealed that the reduction in amyloid was due to a reduction in the size of fibrillar plaques, rather than a decrease in plaque numbers. The current findings support previous studies showing that MBP1 inhibits Aβ fibril formation in vitro, and demonstrate the ability of MBP1 to reduce Aβ pathology and improve behavioral performance.