Brain region-specific myelinogenesis is not directly linked to amyloid-? in APP/PS1 transgenic mice

Alzheimer's disease (AD) is characterized by aggregating amyloid beta-protein (A beta). Recent evidence has shown that insufficient myelinogenesis contributes to AD-related functional deficits. However, it remains unclear whether A beta, in either plaque or soluble form, could alter myelinogenesis in AD brains. By cell-lineage tracing and labeling, we found both myelinogenesis and A beta deposits displayed a region-specific pattern in the 13-month-old APP/PS1 transgenic mouse brains. A beta plaques cause focal demyelination, but only about 15% A beta plaques are closely associated with newly formed myelin in the APP/PS1 brains. Further, the A beta plaque total area and the amount of new myelin are not linearly correlated across different cortical regions, suggesting that A beta plaques induce demyelination but may not exclusively trigger remyelination. To understand the role of soluble A beta in regulating myelinogenesis, we chose to observe the visual system, wherein soluble A beta is detectable but without the presence of A beta plaques in the APP/PS1 retina, optic nerve, and optic tract. Interestingly, newly-formed myelin density was not significantly altered in the APP/PS1 optic nerves and optic tracts as compared to the wildtype controls, suggesting soluble A beta probably does not change myelinogenesis. Further, treatment of purified oligodendrocyte precursor cells (OPCs) with soluble A beta (oligomers) for 48 h did not change the cell densities of MBP positive cells and PDGFR alpha positive OPCs in vitro. Consistently, injection of soluble A beta into the lateral ventricles did not alter myelinogenesis in the corpus callosum of NG2-CreErt; Tau-mGFP mice significantly. Together, these findings indicate that the region-dependent myelinogenesis in AD brains is not directly linked to A beta, but rather probably a synergic result in adapting to AD pathology.