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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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Increased reactive astrocytes in Tg-5xFAD/MBP-/- mice are associated with the absence of MBP. Immunostaining for GFAP showed increased reactive astrocytes in Tg-5xFAD/MBP-/- mice (C) compared with wild-type mice (A) and Tg-5xFAD mice (B). Increased reactive astrocytes 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 areas in (A) to (D) were quantified by Image J software and represented as % of area. Data presented are the mean ± SEM of 3 to 5 mice per group. *P = 0.014, ***P = 0.00,003. (F) Representative immunoblots for GFAP in total brain homogenates from the different mice. (G) Quantitation of GFAP from immunoblots. Data presented are the mean ± SEM of three mice per group. *P = 0.03.
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Figure 6: Increased reactive astrocytes in Tg-5xFAD/MBP-/- mice are associated with the absence of MBP. Immunostaining for GFAP showed increased reactive astrocytes in Tg-5xFAD/MBP-/- mice (C) compared with wild-type mice (A) and Tg-5xFAD mice (B). Increased reactive astrocytes 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 areas in (A) to (D) were quantified by Image J software and represented as % of area. Data presented are the mean ± SEM of 3 to 5 mice per group. *P = 0.014, ***P = 0.00,003. (F) Representative immunoblots for GFAP in total brain homogenates from the different mice. (G) Quantitation of GFAP from immunoblots. Data presented are the mean ± SEM of three mice per group. *P = 0.03.

Mentions: Activated glial cells are known to participate in Aβ clearance by producing a number of Aβ degrading enzymes. Immunostaining for astrocytes using an antibody to GFAP, we found that bigenic Tg-5xFAD/MBP-/- mice (Figure 6C) had extensive astrocyte staining compared with wild-type mice (Figure 6A) and Tg-5xFAD mice (Figure 6B). In addition, we observed a similar elevated astrocyte immunostaining pattern in the MBP-/- mice (Figure 6D) compared with wild-type mice, as reported previously [50,51]. The elevated GFAP was also confirmed by quantitative immunoblotting on brain homogenates from the different mice (Figure 6E). GFAP levels were increased three- to four-fold in Tg-5xFAD/MBP-/- mice and MBP-/- mice compared with Tg-5xFAD mice (Figure 6F).


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 reactive astrocytes in Tg-5xFAD/MBP-/- mice are associated with the absence of MBP. Immunostaining for GFAP showed increased reactive astrocytes in Tg-5xFAD/MBP-/- mice (C) compared with wild-type mice (A) and Tg-5xFAD mice (B). Increased reactive astrocytes 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 areas in (A) to (D) were quantified by Image J software and represented as % of area. Data presented are the mean ± SEM of 3 to 5 mice per group. *P = 0.014, ***P = 0.00,003. (F) Representative immunoblots for GFAP in total brain homogenates from the different mice. (G) Quantitation of GFAP from immunoblots. Data presented are the mean ± SEM of three mice per group. *P = 0.03.
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Figure 6: Increased reactive astrocytes in Tg-5xFAD/MBP-/- mice are associated with the absence of MBP. Immunostaining for GFAP showed increased reactive astrocytes in Tg-5xFAD/MBP-/- mice (C) compared with wild-type mice (A) and Tg-5xFAD mice (B). Increased reactive astrocytes 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 areas in (A) to (D) were quantified by Image J software and represented as % of area. Data presented are the mean ± SEM of 3 to 5 mice per group. *P = 0.014, ***P = 0.00,003. (F) Representative immunoblots for GFAP in total brain homogenates from the different mice. (G) Quantitation of GFAP from immunoblots. Data presented are the mean ± SEM of three mice per group. *P = 0.03.
Mentions: Activated glial cells are known to participate in Aβ clearance by producing a number of Aβ degrading enzymes. Immunostaining for astrocytes using an antibody to GFAP, we found that bigenic Tg-5xFAD/MBP-/- mice (Figure 6C) had extensive astrocyte staining compared with wild-type mice (Figure 6A) and Tg-5xFAD mice (Figure 6B). In addition, we observed a similar elevated astrocyte immunostaining pattern in the MBP-/- mice (Figure 6D) compared with wild-type mice, as reported previously [50,51]. The elevated GFAP was also confirmed by quantitative immunoblotting on brain homogenates from the different mice (Figure 6E). GFAP levels were increased three- to four-fold in Tg-5xFAD/MBP-/- mice and MBP-/- mice compared with Tg-5xFAD mice (Figure 6F).

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