Table 1.

Clearance systems in the brain

Clearance system	Source	Destination	Factors affecting clearance system	Clearance pathways
Blood–brain barrier clearance61	ISF	Blood	Transporter expression and activity Ligand affinity and competition Vascular integrity	Efflux transporters and mediators Influx transporters and mediators
Degradation clearance56
Intracellular	ICS	Degradation	Enzyme expression and activity Ligand affinity and competition Initiation of intracellular degradation pathways	Ubiquitin–proteasome pathway Autophagy–lysosome pathway Endosome–lysosome pathway Proteases
Extracellular	ISF	Degradation or cellular uptake	Enzyme expression and activity Ligand affinity and competition Activation of cellular uptake	Proteases Glial phagocytes
ISF bulk fow clearance86
CSF sink	ISF	CSF sink (subarachnoid space, ventricles)	Intrinsic ISF fow rate	ISF efflux into CSF sink
Perivascular drainage	ISF	Periarterial space to peripheral lymph	APOE*ε4 Immune complex deposition Arterial age Arterial pulsation (hypothetical)	ISF efflux into basement membrane of capillary and arterial walls
Perivascular glymphatic	ISF	Perivenous space to peripheral lymph or ventricles	Molecular size Arterial pulsation AQP4 expression and localization Sleep	CSF influx into periarterial space CSF–ISF exchange within interstitium CSF–ISF efflux along perivenous space
CSF absorption clearance18,98
Circulatory	CSF	Blood	CSF production BCSFB transporters Arachnoid villi resistance	Arachnoid villi integrity and BCSFB efflux and influx ransporters and mediators
Lymphatic	CSF	Peripheral lymph	Lymphatic absorption of CSF	Perivascular space Perineural space
Meningeal lymphatic vessels	CSF	Lymph	Unknown	Subarachnoid CSF into meningeal lymphatic vessels

Abbreviations: APOE*ε4, apolipoprotein E ε4 allele; AQP4, aquaporin-4; BCSFB, blood–CSF barrier; CSF, cerebrospinal fluid; ICS, intracellular space; ISF, interstitial fluid.