CNS trafficking routes of amyloid beta

The glia-lymphatic (glymphatic) system uses peri-arterial spaces for delivering cerebrospinal fluid (CSF) to the brain. This influx of fluid is assisted by aquaporin 4 (AQP4) water channels in astrocyte vascular endfeet.

Knockout of AQP4 impairs clearance of solutes and peptides such as amyloid beta (AB), the culprit in Alzheimer´s disease, from the brain.

In addition to glymphatic peri-venous clearance pathways, the LRP1 transporter protein at the blood-brain barrier (BBB) add an additional clearance route for AB. In pigs, AB followed threads of elastin in peri-arterial spaces leading to the lamina elastica interna.

This peculiar distribution of AB was unlike other proteins, e.g. bovine serum albumin, which penetrated deeper into the brain along peri-arterial spaces but further laterally than the elastin fibers. This project will use pigs to further elucidate the transport of AB in the peri-vascular spaces.

Using nano-gold particle labelled AB, we will perform analysis of its trafficking pathways with unprecedented resolution using advanced electron microscopy and the hard x-ray nanoprobe beamline at MAXIV.

Finally, we will use genetically modified mice to test the hypothesis that the glymphatic system cooperates with the carriers at the BBB for the disposal of AB by bringing it from the CSF to the peri-vascular compartment where from the BBB transporters can take over. This project add significant new insights into the clearance of AB.