Impairment of paravascular clearance pathways in the aging brain
Benjamin T. Kress BA
Center for Translational Neuromedicine, University of Rochester School of Medicine, Rochester, NY
Search for more papers by this authorCorresponding Author
Jeffrey J. Iliff PhD
Center for Translational Neuromedicine, University of Rochester School of Medicine, Rochester, NY
Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR
Knight Cardiovascular Research Institute, Oregon Health & Science University, Portland, OR
Address correspondence to Dr Iliff, Department of Anaesthesiology and Perioperative Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Mail Code HRC5N, Portland, OR 97239. E-mail: [email protected]Search for more papers by this authorMaosheng Xia MD, PhD
Center for Translational Neuromedicine, University of Rochester School of Medicine, Rochester, NY
Department of Orthopedics, First Hospital of China Medical University, Shenyang, People's Republic of China
Search for more papers by this authorMinghuan Wang MD, PhD
Center for Translational Neuromedicine, University of Rochester School of Medicine, Rochester, NY
Search for more papers by this authorHelen S. Wei BS
Center for Translational Neuromedicine, University of Rochester School of Medicine, Rochester, NY
Search for more papers by this authorDouglas Zeppenfeld BS
Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR
Search for more papers by this authorLulu Xie PhD
Center for Translational Neuromedicine, University of Rochester School of Medicine, Rochester, NY
Search for more papers by this authorHongyi Kang BS
Center for Translational Neuromedicine, University of Rochester School of Medicine, Rochester, NY
Search for more papers by this authorQiwu Xu BS
Center for Translational Neuromedicine, University of Rochester School of Medicine, Rochester, NY
Search for more papers by this authorJason A. Liew
Center for Translational Neuromedicine, University of Rochester School of Medicine, Rochester, NY
Search for more papers by this authorBenjamin A. Plog BA
Center for Translational Neuromedicine, University of Rochester School of Medicine, Rochester, NY
Search for more papers by this authorFengfei Ding MD, PhD
Center for Translational Neuromedicine, University of Rochester School of Medicine, Rochester, NY
Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR
Search for more papers by this authorRashid Deane PhD
Center for Translational Neuromedicine, University of Rochester School of Medicine, Rochester, NY
Search for more papers by this authorMaiken Nedergaard MD, PhD
Center for Translational Neuromedicine, University of Rochester School of Medicine, Rochester, NY
Search for more papers by this authorBenjamin T. Kress BA
Center for Translational Neuromedicine, University of Rochester School of Medicine, Rochester, NY
Search for more papers by this authorCorresponding Author
Jeffrey J. Iliff PhD
Center for Translational Neuromedicine, University of Rochester School of Medicine, Rochester, NY
Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR
Knight Cardiovascular Research Institute, Oregon Health & Science University, Portland, OR
Address correspondence to Dr Iliff, Department of Anaesthesiology and Perioperative Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Mail Code HRC5N, Portland, OR 97239. E-mail: [email protected]Search for more papers by this authorMaosheng Xia MD, PhD
Center for Translational Neuromedicine, University of Rochester School of Medicine, Rochester, NY
Department of Orthopedics, First Hospital of China Medical University, Shenyang, People's Republic of China
Search for more papers by this authorMinghuan Wang MD, PhD
Center for Translational Neuromedicine, University of Rochester School of Medicine, Rochester, NY
Search for more papers by this authorHelen S. Wei BS
Center for Translational Neuromedicine, University of Rochester School of Medicine, Rochester, NY
Search for more papers by this authorDouglas Zeppenfeld BS
Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR
Search for more papers by this authorLulu Xie PhD
Center for Translational Neuromedicine, University of Rochester School of Medicine, Rochester, NY
Search for more papers by this authorHongyi Kang BS
Center for Translational Neuromedicine, University of Rochester School of Medicine, Rochester, NY
Search for more papers by this authorQiwu Xu BS
Center for Translational Neuromedicine, University of Rochester School of Medicine, Rochester, NY
Search for more papers by this authorJason A. Liew
Center for Translational Neuromedicine, University of Rochester School of Medicine, Rochester, NY
Search for more papers by this authorBenjamin A. Plog BA
Center for Translational Neuromedicine, University of Rochester School of Medicine, Rochester, NY
Search for more papers by this authorFengfei Ding MD, PhD
Center for Translational Neuromedicine, University of Rochester School of Medicine, Rochester, NY
Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR
Search for more papers by this authorRashid Deane PhD
Center for Translational Neuromedicine, University of Rochester School of Medicine, Rochester, NY
Search for more papers by this authorMaiken Nedergaard MD, PhD
Center for Translational Neuromedicine, University of Rochester School of Medicine, Rochester, NY
Search for more papers by this authorAbstract
Objective
In the brain, protein waste removal is partly performed by paravascular pathways that facilitate convective exchange of water and soluble contents between cerebrospinal fluid (CSF) and interstitial fluid (ISF). Several lines of evidence suggest that bulk flow drainage via the glymphatic system is driven by cerebrovascular pulsation, and is dependent on astroglial water channels that line paravascular CSF pathways. The objective of this study was to evaluate whether the efficiency of CSF–ISF exchange and interstitial solute clearance is impaired in the aging brain.
Methods
CSF–ISF exchange was evaluated by in vivo and ex vivo fluorescence microscopy and interstitial solute clearance was evaluated by radiotracer clearance assays in young (2–3 months), middle-aged (10–12 months), and old (18–20 months) wild-type mice. The relationship between age-related changes in the expression of the astrocytic water channel aquaporin-4 (AQP4) and changes in glymphatic pathway function was evaluated by immunofluorescence.
Results
Advancing age was associated with a dramatic decline in the efficiency of exchange between the subarachnoid CSF and the brain parenchyma. Relative to the young, clearance of intraparenchymally injected amyloid-β was impaired by 40% in the old mice. A 27% reduction in the vessel wall pulsatility of intracortical arterioles and widespread loss of perivascular AQP4 polarization along the penetrating arteries accompanied the decline in CSF–ISF exchange.
Interpretation
We propose that impaired glymphatic clearance contributes to cognitive decline among the elderly and may represent a novel therapeutic target for the treatment of neurodegenerative diseases associated with accumulation of misfolded protein aggregates. Ann Neurol 2014;76:845–861
References
- 1 Lindsay J, Laurin D, Verreault R, et al. Risk factors for Alzheimer's disease: a prospective analysis from the Canadian Study of Health and Aging. Am J Epidemiol 2002; 156: 445–453.
- 2 Ross CA, Poirier MA. Protein aggregation and neurodegenerative disease. Nat Med 2004; 10(suppl): S10–S17.
- 3 Mawuenyega KG, Sigurdson W, Ovod V, et al. Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science 2010; 330: 1774.
- 4 Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med 2012; 4: 147ra111.
- 5 Iliff JJ, Lee H, Yu M, et al. Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J Clin Invest 2013; 123: 1299–1309.
- 6 Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. Science 2013; 342: 373–377.
- 7 Iliff JJ, Wang M, Zeppenfeld DM, et al. Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. J Neurosci 2013; 33: 18190–18199.
- 8 Yang L, Kress BT, Weber HJ, et al. Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer. J Transl Med 2013; 11: 107.
- 9 Bell RD, Sagare AP, Friedman AE, et al. Transport pathways for clearance of human Alzheimer's amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system. J Cereb Blood Flow Metab 2007; 27: 909–918.
- 10 Deane R, Wu Z, Sagare A, et al. LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms. Neuron 2004; 43: 333–344.
- 11 Cirrito JR, May PC, O'Dell MA, et al. In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life. J Neurosci 2003; 23: 8844–8853.
- 12 Nicholson C. Ion-selective microelectrodes and diffusion measurements as tools to explore the brain cell microenvironment. J Neurosci Methods 1993; 48: 199–213.
- 13 Ren Z, Iliff JJ, Yang L, et al. 'Hit & Run' model of closed-skull traumatic brain injury (TBI) reveals complex patterns of post-traumatic AQP4 dysregulation. J Cereb Blood Flow Metab 2013; 33: 834–845.
- 14 Wang M, Iliff JJ, Liao Y, et al. Cognitive deficits and delayed neuronal loss in a mouse model of multiple microinfarcts. J Neurosci 2012; 32: 17948–17960.
- 15 Shibata M, Yamada S, Kumar SR, et al. Clearance of Alzheimer's amyloid-ss(1–40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest 2000; 106: 1489–1499.
- 16 Iliff JJ, Nedergaard M. Is there a cerebral lymphatic system? Stroke 2013; 44: S93–S95.
- 17 Rennels ML, Gregory TF, Blaumanis OR, et al. Evidence for a 'paravascular' fluid circulation in the mammalian central nervous system, provided by the rapid distribution of tracer protein throughout the brain from the subarachnoid space. Brain Res 1985; 326: 47–63.
- 18 Sykova E, Nicholson C. Diffusion in brain extracellular space. Physiol Rev 2008; 88: 1277–1340.
- 19 Nagelhus EA, Ottersen OP. Physiological roles of aquaporin-4 in brain. Physiol Rev 2013; 93: 1543–1562.
- 20 Nielsen S, Nagelhus EA, Amiry-Moghaddam M, et al. Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J Neurosci 1997; 17: 171–180.
- 21 Verkman AS, Binder DK, Bloch O, et al. Three distinct roles of aquaporin-4 in brain function revealed by knockout mice. Biochim Biophys Acta 2006; 1758: 1085–1093.
- 22 Mathiisen TM, Lehre KP, Danbolt NC, Ottersen OP. The perivascular astroglial sheath provides a complete covering of the brain microvessels: an electron microscopic 3D reconstruction. Glia 2010; 58: 1094–1103.
- 23 Brightman MW, Reese TS. Junctions between intimately apposed cell membranes in the vertebrate brain. J Cell Biol 1969; 40: 648–677.
- 24 Amiry-Moghaddam M, Ottersen OP. The molecular basis of water transport in the brain. Nat Rev Neurosci 2003; 4: 991–1001.
- 25 Redzic ZB, Preston JE, Duncan JA, et al. The choroid plexus-cerebrospinal fluid system: from development to aging. Curr Top Dev Biol 2005; 71: 1–52.
- 26 Hadaczek P, Yamashita Y, Mirek H, et al. The "perivascular pump" driven by arterial pulsation is a powerful mechanism for the distribution of therapeutic molecules within the brain. Mol Ther 2006; 14: 69–78.
- 27 Wang P, Olbricht WL. Fluid mechanics in the perivascular space. J Theor Biol 2011; 274: 52–57.
- 28 Schley D, Carare-Nnadi R, Please CP, et al. Mechanisms to explain the reverse perivascular transport of solutes out of the brain. J Theor Biol 2006; 238: 962–974.
- 29 Picano E, Bruno RM, Ferrari GF, Bonuccelli U. Cognitive impairment and cardiovascular disease: so near, so far. Int J Cardiol 2014; 175: 21–29.
- 30 Fonck E, Feigl GG, Fasel J, et al. Effect of aging on elastin functionality in human cerebral arteries. Stroke 2009; 40: 2552–2556.
- 31 Hughes TM, Kuller LH, Barinas-Mitchell EJ, et al. Pulse wave velocity is associated with beta-amyloid deposition in the brains of very elderly adults. Neurology 2013; 81: 1711–1718.
- 32 Zhang ET, Inman CB, Weller RO. Interrelationships of the pia mater and the perivascular (Virchow-Robin) spaces in the human cerebrum. J Anat 1990; 170: 111–123.
- 33 Verkman AS, Mitra AK. Structure and function of aquaporin water channels. Am J Physiol Renal Physiol 2000; 278: F13–F28.
- 34 Salminen A, Ojala J, Kaarniranta K, et al. Astrocytes in the aging brain express characteristics of senescence-associated secretory phenotype. Eur J Neurosci 2011; 34: 3–11.
- 35 Hoshi A, Yamamoto T, Shimizu K, et al. Characteristics of aquaporin expression surrounding senile plaques and cerebral amyloid angiopathy in Alzheimer disease. J Neuropathol Exp Neurol 2012; 71: 750–759.
- 36 Yang J, Lunde LK, Nuntagij P, et al. Loss of astrocyte polarization in the tg-ArcSwe mouse model of Alzheimer's disease. J Alzheimers Dis 2011; 27: 711–722.
- 37 May C, Kaye JA, Atack JR, et al. Cerebrospinal fluid production is reduced in healthy aging. Neurology 1990; 40: 500–503.
- 38 Erickson MA, Hartvigson PE, Morofuji Y, et al. Lipopolysaccharide impairs amyloid beta efflux from brain: altered vascular sequestration, cerebrospinal fluid reabsorption, peripheral clearance and transporter function at the blood-brain barrier. J Neuroinflammation 2012; 9: 150.
- 39 Cserr HF. Physiology of the choroid plexus. Physiol Rev 1971; 51: 273–311.
- 40 Groothuis DR, Vavra MW, Schlageter KE, et al. Efflux of drugs and solutes from brain: the interactive roles of diffusional transcapillary transport, bulk flow and capillary transporters. J Cereb Blood Flow Metab 2007; 27: 43–56.
- 41 Frost B, Diamond MI. Prion-like mechanisms in neurodegenerative diseases. Nat Rev Neurosci 2010; 11: 155–159.
Citing Literature
