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

Ou-Yang MH, Van Nostrand WE - J Neuroinflammation (2013)

Bottom Line: Through 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.These 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Departments of Neurosurgery & Medicine, Stony Brook University, Stony Brook, NY 11794-8122, USA. William.VanNostrand@stonybrook.edu.

ABSTRACT

Background: Abnormal 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.

Methods: In 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.

Results: Through 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.

Conclusions: These 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.

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Elevated MMP-9 levels in Tg-5xFAD/MBP-/- mice. (A) Gelatin zymography of brain homogenates shows increased levels of MMP-9, but not MMP-2, in bigenic Tg-5xFAD/MBP-/- mice. (B) Quantification of gelatin zymography signals show MMP-9, but not MMP-2, was increased 2-fold in bigenic Tg-5xFAD-MBP-/- mice. Data presented are mean ± SEM of four mice per group. *p < 0.05. (C) Immunoblot of MMP-9 in brain homogenates of Tg-5xFAD mice and bigenic Tg-5xFAD/MBP-/- mice.
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Figure 8: Elevated MMP-9 levels in Tg-5xFAD/MBP-/- mice. (A) Gelatin zymography of brain homogenates shows increased levels of MMP-9, but not MMP-2, in bigenic Tg-5xFAD/MBP-/- mice. (B) Quantification of gelatin zymography signals show MMP-9, but not MMP-2, was increased 2-fold in bigenic Tg-5xFAD-MBP-/- mice. Data presented are mean ± SEM of four mice per group. *p < 0.05. (C) Immunoblot of MMP-9 in brain homogenates of Tg-5xFAD mice and bigenic Tg-5xFAD/MBP-/- mice.

Mentions: Reactive astrocytes and activated microglia are known to express the Aβ-degrading enzymes matrix metalloproteinase 2 and 9 (MMP-2 and MMP-9) [52-54]. To measure the activity of MMP-2 and MMP-9, gelatin zymography was performed using brain lysates prepared from Tg-5xFAD mice and bigenic Tg-5xFAD/MBP-/- mice that were concentrated by filtration over gelatin agarose. Gelatin zymography showed a two-fold increase in MMP-9, but not MMP-2, in Tg-5xFAD/MBP-/- mice compared with Tg-5xFAD mice (Figure 8A,B). Immunoblotting showed a similar increase in MMP-9 protein levels in Tg-5xFAD/MBP-/- mice (Figure 8C).


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

Ou-Yang MH, Van Nostrand WE - J Neuroinflammation (2013)

Elevated MMP-9 levels in Tg-5xFAD/MBP-/- mice. (A) Gelatin zymography of brain homogenates shows increased levels of MMP-9, but not MMP-2, in bigenic Tg-5xFAD/MBP-/- mice. (B) Quantification of gelatin zymography signals show MMP-9, but not MMP-2, was increased 2-fold in bigenic Tg-5xFAD-MBP-/- mice. Data presented are mean ± SEM of four mice per group. *p < 0.05. (C) Immunoblot of MMP-9 in brain homogenates of Tg-5xFAD mice and bigenic Tg-5xFAD/MBP-/- mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4228351&req=5

Figure 8: Elevated MMP-9 levels in Tg-5xFAD/MBP-/- mice. (A) Gelatin zymography of brain homogenates shows increased levels of MMP-9, but not MMP-2, in bigenic Tg-5xFAD/MBP-/- mice. (B) Quantification of gelatin zymography signals show MMP-9, but not MMP-2, was increased 2-fold in bigenic Tg-5xFAD-MBP-/- mice. Data presented are mean ± SEM of four mice per group. *p < 0.05. (C) Immunoblot of MMP-9 in brain homogenates of Tg-5xFAD mice and bigenic Tg-5xFAD/MBP-/- mice.
Mentions: Reactive astrocytes and activated microglia are known to express the Aβ-degrading enzymes matrix metalloproteinase 2 and 9 (MMP-2 and MMP-9) [52-54]. To measure the activity of MMP-2 and MMP-9, gelatin zymography was performed using brain lysates prepared from Tg-5xFAD mice and bigenic Tg-5xFAD/MBP-/- mice that were concentrated by filtration over gelatin agarose. Gelatin zymography showed a two-fold increase in MMP-9, but not MMP-2, in Tg-5xFAD/MBP-/- mice compared with Tg-5xFAD mice (Figure 8A,B). Immunoblotting showed a similar increase in MMP-9 protein levels in Tg-5xFAD/MBP-/- mice (Figure 8C).

Bottom Line: Through 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.These 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Departments of Neurosurgery & Medicine, Stony Brook University, Stony Brook, NY 11794-8122, USA. William.VanNostrand@stonybrook.edu.

ABSTRACT

Background: Abnormal 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.

Methods: In 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.

Results: Through 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.

Conclusions: These 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.

Show MeSH
Related in: MedlinePlus