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The Absence of Myelin Basic Protein Reduces Non-Amyloidogenic Processing of Amyloid Precursor Protein
Chika Seiwa1, Ichiro Sugiyama2, Makoto Sugawa1
1Center for Kampo Medicine, Keio University School of Medicine, Shinanomachi, Shinjukuku, Tokyo 160-8582, Japan.
Background:
The accumulation of amyloid β-protein (Aβ) in the brain is a pathological feature of Alzheimer's disease (AD). Aβ peptides originate from amyloid precursor protein (APP). APP can be proteolytically cleaved through amyloidogenic or non-amyloidogenic pathways. The molecular effects on APP metabolism/processing may be influenced by myelin and the breakdown of myelin basic protein (MBP) in AD patients and mouse models of AD pathology.
Methods:
We directly tested whether MBP can alter influence APP processing in MBP-/- mice, known as Shiverer (shi/shi) mice, in which no functional MBP is produced due to gene breakage from the middle of MBP exon ll.
Results:
A significant reduction of the cerebral sAPPα level in Shiverer (shi/shi) mice was found, although the levels of both total APP and sAPPβ remain unchanged. The reduction of sAPPα was considered to be due to the changes in the expression levels of a disintegrin and metalloproteinase-9 (ADAM9) catalysis and non-amyloid genic processing of APP in the absence of MBP because it binds to ADAM9. MBP -/- mice exhibited increased Aβ oligomer production.
Conclusion:
These findings suggest that in the absence of MBP, there is a marked reduction of nonamyloidogenic APP processing to sAPPα, and targeting myelin of oligodendrocytes may be a novel therapy for the prevention and treatment of AD.
Insights
Myelin basic protein (MBP) absence reduces non-amyloidogenic amyloid precursor protein (APP) processing, increasing amyloid-beta oligomers in Alzheimer
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Alzheimer's disease (AD) is characterized by amyloid-beta protein (Aβ) accumulation in the brain.
- Amyloid precursor protein (APP) processing occurs via amyloidogenic or non-amyloidogenic pathways.
- Myelin and myelin basic protein (MBP) breakdown may influence APP metabolism in AD.
Purpose of the Study:
- To investigate the direct impact of myelin basic protein (MBP) on amyloid precursor protein (APP) processing.
- To analyze APP metabolism in the absence of functional MBP using Shiverer (MBP-/-) mice.
Main Methods:
- Utilized Shiverer (MBP-/-) mice, which lack functional myelin basic protein (MBP).
- Assessed levels of soluble APP-alpha (sAPPα), total APP, and soluble APP-beta (sAPPβ).
- Examined the expression of a disintegrin and metalloproteinase-9 (ADAM9) and Aβ oligomer production.
Main Results:
- A significant reduction in cerebral sAPPα was observed in MBP-/- mice.
- Total APP and sAPPβ levels remained unchanged, indicating specific pathway alterations.
- MBP-/- mice showed increased amyloid-beta (Aβ) oligomer production, linked to altered ADAM9 activity.
Conclusions:
- Absence of MBP markedly reduces non-amyloidogenic APP processing to sAPPα.
- Myelin targeting of oligodendrocytes presents a potential novel therapeutic strategy for AD.
- Findings highlight the role of myelin in modulating APP metabolism and Aβ pathology.
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