Clearance of interstitial fluid (ISF) and CSF (CLIC) group-part of Vascular Professional Interest Area (PIA): Cerebrovascular disease and the failure of elimination of Amyloid-β from the brain and retina with age and Alzheimer's disease-Opportunities for Therapy

Abstract

Two of the key functions of arteries in the brain are (1) the well-recognized supply of blood via the vascular lumen and (2) the emerging role for the arterial walls as routes for the elimination of interstitial fluid (ISF) and soluble metabolites, such as amyloid beta (Aβ), from the brain and retina. As the brain and retina possess no conventional lymphatic vessels, fluid drainage toward peripheral lymph nodes is mediated via transport along basement membranes in the walls of capillaries and arteries that form the intramural peri-arterial drainage (IPAD) system. IPAD tends to fail as arteries age but the mechanisms underlying the failure are unclear. In some people this is reflected in the accumulation of Aβ plaques in the brain in Alzheimer's disease (AD) and deposition of Aβ within artery walls as cerebral amyloid angiopathy (CAA). Knowledge of the dynamics of IPAD and why it fails with age is essential for establishing diagnostic tests for the early stages of the disease and for devising therapies that promote the clearance of Aβ in the prevention and treatment of AD and CAA. This editorial is intended to introduce the rationale that has led to the establishment of the Clearance of Interstitial Fluid (ISF) and CSF (CLIC) group, within the Vascular Professional Interest Area of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment.

Keywords: IPAD; ISTAART; cerebrospinal fluid; clearance; interstitial fluid.

FIGURE 1

A, Intramural peri‐arterial drainage (IPAD) pathways for the lymphatic drainage of interstitial fluid (ISF) and soluble amyloid beta (Aβ) from the brain. Right side of diagram: ISF and Aβ (green line and arrows) pass from the extracellular spaces of the brain to drain along the walls of capillaries and arteries ultimately to the cervical lymph nodes adjacent to arteries under the base of the skull. Details of the IPAD pathway are shown in (B). Left side shows how cerebrospinal fluid (CSF) enters the brain along the outer aspects of penetrating arteries and passes into the ISF of the brain parenchyma (details in [C]) and then flows out of the brain along IPAD pathways (green line and arrows). B) Details of the IPAD pathway, cerebral amyloid angiopathy (CAA) and LRP‐1‐related absorption for Aβ. Soluble Aβ (light blue arrow), produced by cells in the brain, is absorbed into the blood involving LRP‐1 as one of the pathways for elimination of Aβ. Another major pathway is by IPAD (green line and arrows). Aβ in the ISF enters the basement membranes of endothelial cells in the walls of capillaries. Contractile pericytes surround capillaries and may supply the motive force for IPAD in capillaries. Aβ then rapidly passes into basement membranes (100 to 150 nm thick) surrounding smooth muscle cells (SMC)s in the tunica media of cerebral arteries. Changes occur in the walls of arteries as they age and IPAD is impaired resulting in the deposition of fibrillar Aβ in the IPAD pathways as CAA (green asterisks). As more Aβ is deposited and the severity of CAA increases, the wall of the artery is disrupted, SMCs are replaced by Aβ and IPAD is further impaired. The yellow line passing along the IPAD pathway shows how CSF that has entered the ISF of the brain also drains from the brain along IPAD pathways in artery walls. SMCs in the tunica media of arteries supply the motive force for IPAD and have both adrenergic and cholinergic innervations. C, Entry of CSF into the brain along periarterial pial–glial basement membranes. As arteries enter the surface of the cerebral cortex they are coated by a layer of pia mater that is firmly associated with the basement membranes of the glia limitans on the surface of the brain. There are no perivascular spaces around cortical arterioles so tracers injected into the CSF enter the brain along the periarterial pial–glial basement membranes and mix with the ISF in the brain parenchyma. CSF tracers are then eliminated from the brain along IPAD pathways. This route could be used to deliver drugs to increase the efficiency of elimination of Aβ along aging IPAD pathways. PVM, perivascular macophage; SAS, subarachnoid space