title: An Alzheimer's disease-relevant presenilin-1 mutation augments amyloid-beta-induced oligodendrocyte dysfunction.
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.
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Maya K
authors.initials: MK
authors.lastname: Desai
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Guercio
authors.forename: Wade C
authors.initials: WC
authors.lastname: Narrow
authors.forename: William J
authors.initials: WJ
authors.lastname: Bowers
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D005434:Flow Cytometry; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009186:Myelin Sheath / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D016229:Amyloid beta-Peptides; D053764:Presenilin-1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3