How does the brain remove its waste metabolites from within?

The brain is the command center of the body that regulates the vital functions of circulation, respiration, motor function, metabolic activities, or autonomic nervous system outcomes. The brain coordinates these continuous activities at the expense of huge energy utilization. This energy demand is achieved by active transport of nutrients across the endothelial blood-brain barrier (BBB). This review discusses the barrier interfaces in the CNS that include the BBB, blood-spinal cord barrier, the epithelial choroid plexus, and the epithelial arachnoid. While transporting of nutrients across the BBB is a normal physiological function, the trafficking of xenobiotics and inflammatory cells/agents across these interfaces is harmful to brain cells. This leads to production of waste metabolites in the brain. Clearance of these waste metabolites maintains the normal brain homeostasis, while aggregation is detrimental to neurological complications. Since the CNS lacks lymphatic system, the CSF serves as the clearance path for water-soluble peptides/solutes, but not large size waste metabolites like Aβ protein. In particular, this review will focus on the mechanisms of waste metabolites clearance paths in the CNS. This will include the recently discovered waste metabolites movement from interstitial space (IS) directly into perivascular clearance (PVC), or via IS-CSF-PVC, and its exchange from PVC to circulation. Concluding remarks will discuss the therapeutic approach to improve the clearance mechanisms for ameliorating neurological diseases.