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

Immunolabeling of brain Aβ deposits in young Tg-5xFAD and bigenic Tg-5xFAD/MBP-/- mice. Rabbit polyclonal antibody against Aβ1-28 was used to detect Aβ deposits. Bigenic Tg-5xFAD/MBP-/- mice (bottom panels) had a marked decrease in Aβ deposition compared to Tg-5xFAD mice (top panels) in: cortex (A, D), subiculum (B, E) and thalamus (C, F). Scale bars, 10 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Immunolabeling of brain Aβ deposits in young Tg-5xFAD and bigenic Tg-5xFAD/MBP-/- mice. Rabbit polyclonal antibody against Aβ1-28 was used to detect Aβ deposits. Bigenic Tg-5xFAD/MBP-/- mice (bottom panels) had a marked decrease in Aβ deposition compared to Tg-5xFAD mice (top panels) in: cortex (A, D), subiculum (B, E) and thalamus (C, F). Scale bars, 10 μm.

Mentions: We next performed immunofluorescent labeling for Aβ on brain sections from Tg-5xFAD and bigenic Tg-5xFAD/MBP-/- mice using an anti-Aβ N-terminal antibody. Even though Aβ deposition just begins at this early age in Tg-5xFAD mice, there was a remarkable decrease in both number and the size of Aβ plaques in bigenic Tg-5xFAD/MBP-/- mice observed in the cortex, subiculum, and thalamus (Figure 2), which was consistent with the reduction of insoluble Aβ from the ELISA analysis.


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)

Immunolabeling of brain Aβ deposits in young Tg-5xFAD and bigenic Tg-5xFAD/MBP-/- mice. Rabbit polyclonal antibody against Aβ1-28 was used to detect Aβ deposits. Bigenic Tg-5xFAD/MBP-/- mice (bottom panels) had a marked decrease in Aβ deposition compared to Tg-5xFAD mice (top panels) in: cortex (A, D), subiculum (B, E) and thalamus (C, F). Scale bars, 10 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Immunolabeling of brain Aβ deposits in young Tg-5xFAD and bigenic Tg-5xFAD/MBP-/- mice. Rabbit polyclonal antibody against Aβ1-28 was used to detect Aβ deposits. Bigenic Tg-5xFAD/MBP-/- mice (bottom panels) had a marked decrease in Aβ deposition compared to Tg-5xFAD mice (top panels) in: cortex (A, D), subiculum (B, E) and thalamus (C, F). Scale bars, 10 μm.
Mentions: We next performed immunofluorescent labeling for Aβ on brain sections from Tg-5xFAD and bigenic Tg-5xFAD/MBP-/- mice using an anti-Aβ N-terminal antibody. Even though Aβ deposition just begins at this early age in Tg-5xFAD mice, there was a remarkable decrease in both number and the size of Aβ plaques in bigenic Tg-5xFAD/MBP-/- mice observed in the cortex, subiculum, and thalamus (Figure 2), which was consistent with the reduction of insoluble Aβ from the ELISA analysis.

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