In Vivo Dynamic Movement of Polymerized Amyloid β in the Perivascular Space of the Cerebral Cortex in Mice

Abstract

Disposition of amyloid β (Aβ) into the perivascular space of the cerebral cortex has been recently suggested as a major source of its clearance, and its disturbance may be involved in the pathogenesis of cerebral amyloid angiopathy and Alzheimer’s disease. Here, we explored the in vivo dynamics of Aβ in the perivascular space of anesthetized mice. Live images were obtained with two-photon microscopy through a closed cranial window. Either fluorescent-dye-labeled Aβ oligomers prepared freshly or Aβ fibrils after 6 days of incubation at 37 °C were placed over the cerebral cortex. Accumulation of Aβ was observed in the localized perivascular space of the penetrating arteries and veins. Transportation of the accumulated Aβ along the vessels was slow and associated with changes in shape. Aβ oligomers were transported smoothly and separately, whereas Aβ fibrils formed a mass and moved slowly. Parenchymal accumulation of Aβ oligomers, as well as Aβ fibrils along capillaries, increased gradually. In conclusion, we confirmed Aβ transportation between the cortical surface and the deeper parenchyma through the perivascular space that may be affected by the peptide polymerization. Facilitation of Aβ excretion through the system can be a key target in treating Alzheimer’s disease.

Diffusion Mediates Molecular Transport through the Perivascular Space in the Brain

“…However, the physiological role and detailed mechanisms of this system are still hypothetical, lacking dynamic data on "in vivo flow". Our previous study confirmed, for the first time, that Aβ can be transported from the cortical surface to the deeper parenchyma through the perivascular space, although there is a difference in the transportation speed between oligomers and fibrils [11]. In the narrow perivascular space, large Aβ fibrils may be easily trapped between the vascular wall and parenchyma.…”

“…In a previous study, we demonstrated that Aβ monomer can be quickly transported through the perivascular space, whereas polymerized Aβ can be trapped at the vascular wall [ 11 ]. These findings, together with those of the present study, suggest that Aβ monomer excreted into the perivascular space can be transported to the subarachnoid space by diffusion based on the concentration gradient, which decreases toward the cortical surface ( Figure 5 B).…”