Triple‐transgenic Alzheimer's disease mice exhibit region‐specific abnormalities in brain myelination patterns prior to appearance of amyloid and tau pathology

Alzheimer's disease (AD) is a progressively debilitating brain disorder pathologically defined by extracellular amyloid plaques, intraneuronal neurofibrillary tangles, and synaptic disintegrity. AD has not been widely considered a disease of white matter, but more recent evidence suggests the existence of abnormalities in myelination patterns and myelin attrition in AD‐afflicted human brains. Herein, we demonstrate that triple‐transgenic AD (3xTg‐AD) mice, which harbor the human amyloid precursor protein Swedish mutant transgene, presenilin knock‐in mutation, and tau P301L mutant transgene, exhibit significant region‐specific alterations in myelination patterns and in oligodendrocyte marker expression profiles at time points preceding the appearance of amyloid and tau pathology. These immunohistochemical signatures are coincident with age‐related alterations in axonal and myelin sheath ultrastructure as visualized by comparative electron microscopic examination of 3xTg‐AD and nontransgenic mouse brain tissue. Overall, these findings indicate that 3xTg‐AD mice represent a viable model in which to examine mechanisms underlying AD‐related myelination and neural transmission defects that occur early during presymptomatic stages of the disease process. © 2008 Wiley‐Liss, Inc.