Clearance systems in the brain-implications for Alzheimer disease

Abstract

Accumulation of toxic protein aggregates-amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles-is the pathological hallmark of Alzheimer disease (AD). Aβ accumulation has been hypothesized to result from an imbalance between Aβ production and clearance; indeed, Aβ clearance seems to be impaired in both early and late forms of AD. To develop efficient strategies to slow down or halt AD, it is critical to understand how Aβ is cleared from the brain. Extracellular Aβ deposits can be removed from the brain by various clearance systems, most importantly, transport across the blood-brain barrier. Findings from the past few years suggest that astroglial-mediated interstitial fluid (ISF) bulk flow, known as the glymphatic system, might contribute to a larger portion of extracellular Aβ (eAβ) clearance than previously thought. The meningeal lymphatic vessels, discovered in 2015, might provide another clearance route. Because these clearance systems act together to drive eAβ from the brain, any alteration to their function could contribute to AD. An understanding of Aβ clearance might provide strategies to reduce excess Aβ deposits and delay, or even prevent, disease onset. In this Review, we describe the clearance systems of the brain as they relate to proteins implicated in AD pathology, with the main focus on Aβ.

Figure 1

Perivascular clearance comprises perivascular drainage and glymphatic pathways. The perivascular drainage Nature Reviews | Neurology pathway (white arrows) moves waste into the periarterial space (located along smooth muscle cells and the capillary basement membrane) and towards the subarachnoid space in the direction opposite to blood flow. The glymphatic pathway (black arrows) clears waste from the ISF through the brain parenchyma, and comprises three functional components. (1) CSF influx, unidirectionally with blood flow, into the periarterial space (between the basement membrane of smooth muscle cells and pia mater), where the water component of CSF crosses astrocytic AQP4 channels to enter the brain parenchyma. CSF solutes can be cleared with astroglial transporters or channels, or can pass through the astrocytic endfeet clefts. (2) CSF–ISF exchange within the brain parenchyma. (3) CSF–ISF movement into the perivenous space of deep-draining veins. Effluxed waste can then recirculate with the CSF, or eventually be absorbed into the lymphatic system. Arrows indicate direction of flow. Abbreviations: AQP4, aquaporin-4; CSF, cerebrospinal fluid; ISF, interstitial fluid. Permission obtained from Cell Press © Nedergaard, M. Science 340, 1529–1530 (2013).

Figure 2

Aβ clearance systems. Soluble Aβ can be removed from the brain by various clearance systems. Degradation clearance via extracellular and intracellular degradation pathways can involve either cellular uptake from the interstitium by neurons, microglia, and astrocytes, or uptake from the perivascular space by smooth muscle cells, perivascular macrophages, and astrocytes. BBB clearance involves Aβ efflux into the blood. ISF bulk flow clearance can occur into the CSF sink (ventricles and subarachnoid space), via perivascular drainage pathway, or via glymphatic pathway. CSF absorption clearance involves absorption either into the circulatory system from the arachnoid villi and BCSFB, or into the lymphatic system from the perivascular and perineural spaces—and possibly through meningeal lymphatic vessels. Abbreviations: Aβ, amyloid-β; BBB, blood–brain barrier; BCSFB, blood–CSF barrier; CSF, cerebrospinal fluid; ISF, interstitial fluid; RAGE, advanced glycosylation end productspecific receptor. Adapted with permission from Nature Publishing Group © Erickson, M. A. & Banks, W. A. J. Cerebr. Blood Flow & Metabol. 33, 1500–1513 (2013).

Figure 3

Aβ efflux and influx through the BBB. Aβ can enter the brain via RAGE as a free plasma-derived peptide, or can be transported by monocytes. Sequestering agents (soluble transporters that chaperone Aβ for systemic degradation) can prevent Aβ entry from the circulation into the brain. Aβ is eliminated from the brain enzymatically or by transportation through the BBB. LRP1 mediates efflux of unbound Aβ and Aβ bound to ApoE2, ApoE3 or α2M from the brain parenchyma into the blood with the help of ABCB1; ApoE4 inhibits this transport process. Aβ bound to clusterin is transported through the BBB by LRP2. Abbreviations: α2M, α2-macroglobulin; Aβ, amyloid-β; ABCB1, multidrug resistance protein 1 (also known as P-glycoprotein 1); ApoE, apolipoprotein E; BBB, blood–brain barrier; LRP, LDL receptor-related protein; RAGE, advanced glycosylation end product-specific receptor; SAP, serum amyloid P; sLRP1, soluble LRP1; sRAGE, soluble form of RAGE. Permission obtained from Nature Publishing Group © Zlokovic, B. V. et al Nat. Rev. Neurosci. 12, 723–738 (2011).