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The Absence of Myelin Basic Protein Reduces Non-Amyloidogenic Processing of Amyloid Precursor Protein

[ Vol. 18 , Issue. 4 ]

Author(s):

Chika Seiwa*, Ichiro Sugiyama , Makoto Sugawa, Hiroaki Murase , Chiaki Kudoh and Hiroaki Asou   Pages 326 - 334 ( 9 )

Abstract:


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: Together, these findings suggest that in the absence of MBP, there is a marked reduction of non-amyloidogenic APP processing to sAPPα, and targeting myelin of oligodendrocytes may be a novel therapy for the prevention and treatment of AD.

Keywords:

Alzheimer`s disease (AD), myelin basic protein (MBP), amyloid precursor protein (APP), myelination, soluble App α (sAPPα), non amyloidogenic processing.

Affiliation:

Center for Kampo Medicine, Department of Neurosurgy, Keio University School of Medicine, Shinanomachi, Shinjukuku, Tokyo 160-8582, Department of Neurosurgy, Keio University School of Medicine, Shinanomachi, Shinjukuku, Tokyo 160-8582, Center for Kampo Medicine, Department of Neurosurgy, Keio University School of Medicine, Shinanomachi, Shinjukuku, Tokyo 160-8582, Glovia Myelin Research Institute, 75-1, Onocho, Tsurumi-ku, Yokohama, Kanagawa 230-0046, KUDOH Clinic for Neurosurgery and Neurology, 1-23-10, Omori-kita, Otaku, Tokyo 143-0016, Center for Kampo Medicine, Department of Neurosurgy, Keio University School of Medicine, Shinanomachi, Shinjukuku, Tokyo 160-8582



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