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.

背景：淀粉样 β 蛋白 (Aβ) 在大脑中的积累是阿尔茨海默病 (AD) 的病理特征。Aβ 肽来源于淀粉样前体蛋白 (APP)。APP 可以通过淀粉样蛋白生成或非淀粉样蛋白生成途径进行蛋白水解切割。APP 代谢/加工的分子效应可能受 AD 患者和 AD 病理小鼠模型中髓鞘和髓鞘碱性蛋白 (MBP) 分解的影响。

方法：我们直接测试了 MBP 是否可以改变 MBP-/- 小鼠（称为 Shiverer (shi/shi) 小鼠）中的 APP 加工，其中由于 MBP 外显子 ll 中间的基因断裂，没有产生功能性 MBP。

结果：发现 Shiverer (shi/shi) 小鼠的大脑 sAPPα 水平显着降低，尽管总 APP 和 sAPPβ 的水平保持不变。sAPPα 的减少被认为是由于去整合素和金属蛋白酶 9 (ADAM9) 催化和 APP 的非淀粉样蛋白基因加工的表达水平发生变化，因为它与 ADAM9 结合。MBP -/- 小鼠表现出增加的 Aβ 寡聚体产量。

结论：这些发现表明，在不存在 MBP 的情况下，非淀粉样蛋白生成 APP 向 sAPPα 的加工显着减少，靶向少突胶质细胞髓鞘可能是预防和治疗 AD 的新疗法。