Connections between perivascular interstitial fluid drainage pathways in the brain: Significance for Alzheimer's disease and neuroimmunology

Introduction: Solutes injected into the interstitial fluid (ISF) of mouse brains drain along basement membranes of capillaries and arteries in a pattern that closely resembles the deposition of amyloid-? in cerebral amyloid angiopathy (CAA). Injected particles (fluorospheres) expand peripheral perivascular spaces in a similar way to the dilatation of perivascular spaces by fluid in the cerebral white matter in Alzheimer’s disease. Here, we test the hypothesis that the drainage route for ISF in vascular basement membranes connects with drainage pathways at the periphery of arteries.Materials and methods: Soluble dextran or 0.02 ?m fluorospheres were injected into brains of 109 mice; animals were fixed by perfusion at intervals up to 1 week. The effect of inflammation was tested by co-injection of the tracers with LPS or kainic acid. The distribution of tracers was characterized using immunofluorescence, image analysis and confocal microscopy.Results: Soluble dextran spread progressively along capillary and artery basement membranes over 3–24 h to leptomeningeal arteries and radially through arterial walls to be taken up by perivascular cells. No spread occurred when tracer was injected into dead animals. Following injection, 0.02 ?m fluorospheres expanded spaces at the periphery of arteries and capillaries and were ingested by perivascular cells. Co-injection with LPS or kainic acid resulted in wider distribution of soluble and particulate tracers.Conclusions: These results suggest that antigens draining in ISF along vascular basement membranes may enter pathways at the periphery of arteries and be sampled by perivascular cells. This interconnection may also help to explain the distribution of amyloid-? in CAA and of fluid around arteries in the white matter in Alzheimer’s disease