Limits...
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.

Show MeSH

Related in: MedlinePlus

Increased activated microglia in Tg-5xFAD/MBP-/- mice are associated with the absence of MBP. Immunostaining with 5D4 keratan sulfate antibody showed increased activated microglia in Tg-5xFAD/MBP-/- mice (C) compared with wild-type mice (A) and Tg-5xFAD mice (B). Increased activated microglia were also observed in MBP-/- mice (D). Left panels, overviews (scale bar, 1 mm); right panels, higher magnification (scale bar, 50 μm). (E) Levels of immunostaining of the selected area in (A) to (D) were quantified by Image J software and represented as % area fraction. Data presented are the mean ± SEM of 3 to 5 mice per group. *P = 0.0106, **P = 0.0123.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4228351&req=5

Figure 7: Increased activated microglia in Tg-5xFAD/MBP-/- mice are associated with the absence of MBP. Immunostaining with 5D4 keratan sulfate antibody showed increased activated microglia in Tg-5xFAD/MBP-/- mice (C) compared with wild-type mice (A) and Tg-5xFAD mice (B). Increased activated microglia were also observed in MBP-/- mice (D). Left panels, overviews (scale bar, 1 mm); right panels, higher magnification (scale bar, 50 μm). (E) Levels of immunostaining of the selected area in (A) to (D) were quantified by Image J software and represented as % area fraction. Data presented are the mean ± SEM of 3 to 5 mice per group. *P = 0.0106, **P = 0.0123.

Mentions: Similarly, using a marker for activated microglia showed increased immunostaining in bigenic Tg-5xFAD/MBP-/- mice (Figure 7C) compared with wild-type mice (Figure 7A) and Tg-5xFAD mice (Figure 7B). Again, we observed a similar elevated activated microglial immunostaining pattern in MBP-/- mice (Figure 7D). Together, these findings indicate that bigenic Tg-5xFAD/MBP-/- mice have elevated levels of neuroinflammatory cells compared with Tg-5xFAD mice and that this effect appears to be associated with the absence of MBP, as MBP-/- mice exhibit comparable increases.


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)

Increased activated microglia in Tg-5xFAD/MBP-/- mice are associated with the absence of MBP. Immunostaining with 5D4 keratan sulfate antibody showed increased activated microglia in Tg-5xFAD/MBP-/- mice (C) compared with wild-type mice (A) and Tg-5xFAD mice (B). Increased activated microglia were also observed in MBP-/- mice (D). Left panels, overviews (scale bar, 1 mm); right panels, higher magnification (scale bar, 50 μm). (E) Levels of immunostaining of the selected area in (A) to (D) were quantified by Image J software and represented as % area fraction. Data presented are the mean ± SEM of 3 to 5 mice per group. *P = 0.0106, **P = 0.0123.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Increased activated microglia in Tg-5xFAD/MBP-/- mice are associated with the absence of MBP. Immunostaining with 5D4 keratan sulfate antibody showed increased activated microglia in Tg-5xFAD/MBP-/- mice (C) compared with wild-type mice (A) and Tg-5xFAD mice (B). Increased activated microglia were also observed in MBP-/- mice (D). Left panels, overviews (scale bar, 1 mm); right panels, higher magnification (scale bar, 50 μm). (E) Levels of immunostaining of the selected area in (A) to (D) were quantified by Image J software and represented as % area fraction. Data presented are the mean ± SEM of 3 to 5 mice per group. *P = 0.0106, **P = 0.0123.
Mentions: Similarly, using a marker for activated microglia showed increased immunostaining in bigenic Tg-5xFAD/MBP-/- mice (Figure 7C) compared with wild-type mice (Figure 7A) and Tg-5xFAD mice (Figure 7B). Again, we observed a similar elevated activated microglial immunostaining pattern in MBP-/- mice (Figure 7D). Together, these findings indicate that bigenic Tg-5xFAD/MBP-/- mice have elevated levels of neuroinflammatory cells compared with Tg-5xFAD mice and that this effect appears to be associated with the absence of MBP, as MBP-/- mice exhibit comparable increases.

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