Abstract
White matter pathology has been documented in the brains of familial Alzheimer's disease (FAD)-afflicted individuals during presymptomatic and preclinical stages of AD. How these defects in myelination integrity arise and what roles they may play in AD pathophysiology have yet to be fully elucidated. We previously demonstrated that triple-transgenic AD (3xTg-AD) mice, which harbor the human amyloid precursor Swedish mutation, presenilin-1 M146V (PS1(M146V) ) knock-in mutation, and tau(P301L) mutation, exhibit myelin abnormalities analogous to FAD patients and that Aβ(1-42) contributes to these white matter deficits. Herein, we demonstrate that the PS1(M146V) mutation predisposes mouse oligodendrocyte precursor (mOP) cells to Aβ(1-42) -induced alterations in cell differentiation in vitro. Furthermore, PS1(M146V) expression compromised mOP cell function and MBP protein distribution, a process that is further aggravated with exposure to Aβ(1-42) . We found that the myelination defect and MBP subcellular mislocalization triggered by PS1(M146V) and Aβ(1-42) can be effectively prevented by treatment with the GSK-3β inhibitor, TWS119, thereby implicating GSK-3β kinase activity in this pathogenic cascade. Overall, this work provides further mechanistic insights into PS1(M146V) and Aβ(1-42) -driven oligodendrocyte dysfunction andmyelin damage during early presymptomatic stages of AD, and provides a new target in oligodendrocytes for developing therapies designed to avert AD-related white matter pathology.