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.