This paper is actually a collection of several experiments so it took a little longer to read. Background–this group (from University of Rochester) has described what they christened the “glymphatic system”. Essentially, like we talked about yesterday, one of the major ways the brain can get rid of certain substances is through CSF that, after leaving the ventricles, recirculates in the space along the penetrating cerebral arteries, and collects extracellular solutes including amyloid. The exchange between CSF and the interstitial fluid is mediated in part by aquaporin-4 which is located on the foot processes of astrocytes. This seems to happen particularly during sleep. This paper looked at how aging affects this process in mice.
Experiment 1: Fluorescent tracers were injected into the CSF, and then the brains were examined after 30 minutes. In older mice, the tracer didn’t penetrate very far compared to younger mice in the same time frame.
Experiment 2: Radiolabeled amyloid (cleared by both CSF and across BBB, as per the paper yesterday) as well as inulin (cleared only via CSF) were injected into the caudate. Clearance of both tracers was significantly impaired in older mice.
Experiment 3: The pulsatility of cerebral vasculature, which seems to help drive CSF flow along paravascular pathways, was measured. The pulsatility of penetrating arteries was reduced in older mice; veins were unchanged.
Experiment 4: Aging did not affect the extracellular volume; similar to prior studies, both young and old mice had increases with anesthesia.
Experiment 5: Aquaporin-4 (AQP4) distribution was measured using immunofluorescence. In young mice, AQP4 expression was highly localized to perivascular endfeet immediately around arterioles. In older mice, the protein was less concentrated.
This paper was a little harder because of all the lab methods, but the takeaway is that CSF clearance of solutes, including amyloid, is reduced with aging in mice.