Perivascular lymphatic drainage and solute clearance:

R. Carare 2015, R.O.Carare@soton.ac.uk

Apart from the blood, there are two fluids associated with the brain: cerebrospinal fluid (CSF) and interstitial fluid (ISF). CSF drains through arachnoid villi into the blood and via routes adjacent to olfactory nerves into the nasal mucosa and cervical lymphatics [1].  This route permits the drainage of antigen presenting cells from the subarachnoid space into the lymphatic system. The brain parenchyma is not endowed with traditional lymphatic vessels. For the last 50 years different physiological studies have shown that interstitial fluid drains from the brain along perivascular pathways into cervical lymphatics [2]. Using refined injection techniques and confocal microscopy, our group has demonstrated that drainage of interstitial fluid and solutes from the brain occurs along 100-150 nm-wide basement membranes in the walls of cerebral capillaries and arteries. Older experimental studies suggest that only 10-15% of solutes draining by this route escape into the CSF [3]. We have demonstrated that injection of soluble Aβ into the brain parenchyma of young mice results in its rapid elimination along the walls of capillaries and arteries [4]. Our theoretical modelling studies suggest that the motive force for perivascular lymphatic drainage is derived from vascular pulsations and biochemical interactions with basement membranes [5, 6]. With increasing age and arteriosclerosis, cerebral arteries become stiffer [7] and the amplitude of pulsations decreases. Motive force declines reducing efficiency of lymphatic drainage of the brain as shown in aged mice [4].

Our working hypothesis is that the deposition of amyloid plaques in the human brain with age and Alzheimer’s disease reflects a failure of elimination of Aβ from the brain. Several mechanisms for the elimination of Aβ from the brain have been defined. These include degradation by enzymes such as neprilysin [8], receptor-mediated absorption into the blood [9], passage into the CSF [10] and perivascular lymphatic drainage [11]. Reduction in neprilysin activity and failure of absorption of Aβ into the blood with age [8, 9] may divert more Aβ along perivascular lymphatic drainage pathways [8, 12]. 

As arteries age, lymphatic drainage becomes less efficient [4] and Aβ is deposited in basement membranes of arteries and capillaries as cerebral amyloid angiopathy (CAA), which further impairs perivascular lymphatic drainage [13]. APOE ε4 is also associated with impaired perivascular lymphatic drainage as demonstrated in mice expressing human ApoE ε4 [14].

As a result of the failure of elimination of Aβ from the brain associated with ageing of cerebral arteries and CAA there is loss of homoeostasis of the extracellular environment in the brain as reflected in the rise of soluble Aβ in Alzheimer’s disease [15]. It is likely that there is also failure of elimination of soluble metabolites other than Aβ adding further to the loss of homoeostasis of the neuronal environment. The association of CAA with accumulation of fluid in the subcortical white matter reported after recent therapeutic trials in Alzheimer’s disease suggests that drainage of fluid is ultimately impaired [16, 17].

We are working in an interdisciplinary manner to demonstrate that changes in extracellular matrix and artery walls due to age, genotype, diet or different patterns of innervation or branching of blood vessels could have a marked effect upon the extracellular environment of brain tissue leading especially to failure of elimination of Aβ from the extracellular space but also to failure of elimination of other metabolites and loss of homeostasis.  Our mission is to clarify the exact factors that are responsible for efficient drainage along basement membranes of capillaries and arteries in order to identify new therapeutic targets for cerebral amyloid angiopathy and Alzheimer’s disease.

References

1. Kida, S., A. Pantazis, and R.O. Weller, CSF drains directly from the subarachnoid space into nasal lymphatics in the rat. Anatomy, histology and immunological significance. Neuropathol.Appl Neurobiol., 1993. 19(6): p. 480-488.

2. Bradbury, M.W., H.F. Cserr, and R.J. Westrop, Drainage of cerebral interstitial fluid into deep cervical lymph of the rabbit. Am.J Physiol, 1981. 240(4): p. F329-F336.

3. Szentistvanyi, I., et al., Drainage of interstitial fluid from different regions of rat brain. American Journal of Physiology, 1984. 246: p. F835-844.

4. Hawkes, C.A., et al., Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy. Acta Neuropathologica, 2011. 121: p. 431-43.

5. Arbel-Ornath, M., et al., Interstitial fluid drainage is impaired in ischemic stroke and Alzheimer's disease mouse models. Acta Neuropatholologica, 2013. 126(3): p. 353-64.

6. Schley, D., et al., Mechanisms to explain the reverse perivascular transport of solutes out of the brain. Journal of Theoretical Biology, 2006. 238 p. 962-74

7. Weller, R.O., D. Boche, and J.A. Nicoll, Microvasculature changes and cerebral amyloid angiopathy in Alzheimer's disease and their potential impact on therapy. Acta Neuropathologica, 2009. 118: p. 87-102.

8. Miners, J.S., et al., Decreased expression and activity of neprilysin in Alzheimer disease are associated with cerebral amyloid angiopathy. J Neuropathol Exp Neurol, 2006. 65: p. 1012-1021.

9. Zlokovic, B.V., Clearing amyloid through the blood-brain barrier. J Neurochem, 2004. 89: p. 807-811.

10. Iliff, J.J., 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(147): p. 147ra111.

11. Weller, R.O., et al., Lymphatic drainage of the brain and the pathophysiology of neurological disease. Acta Neuropathologica, 2009. 117: p. 1-14.

12. Shibata, M., et al., Clearance of Alzheimer's amyloid-beta(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest, 2000. 106(12): p. 1489-99.

13. Hawkes, C.A., et al., Failure of Perivascular Drainage of beta-amyloid in Cerebral Amyloid Angiopathy. Brain Pathol 2014. 24: p. 396-403.

14. Hawkes, C.A., et al., Disruption of arterial perivascular drainage of amyloid-beta from the brains of mice expressing the human APOE epsilon4 allele. PLoS One, 2012. 7: p. e41636.

15. Tomic, J.L., et al., Soluble fibrillar oligomer levels are elevated in Alzheimer's disease brain and correlate with cognitive dysfunction. Neurobiol Dis, 2009. 35: p. 352-8.

16. Roher, A.E., et al., Cortical and leptomeningeal cerebrovascular amyloid and white matter pathology in Alzheimer's disease. Molecular Medicine, 2003. 9: p. 112-122.

17. Weller, R.O., et al., White matter changes in dementia: role of impaired drainage of interstitial fluid. Brain Pathol, 2015. 25(1): p. 63-78

Perivascular lymphatic drainage and solute clearance:

R. Carare 2015, R.O.Carare@soton.ac.uk


Apart from the blood, there are two fluids associated with the brain: cerebrospinal fluid (CSF) and interstitial fluid (ISF). CSF drains through arachnoid villi into the blood and via routes adjacent to olfactory nerves into the nasal mucosa and cervical lymphatics [1].  This route permits the drainage of antigen presenting cells from the subarachnoid space into the lymphatic system. The brain parenchyma is not endowed with traditional lymphatic vessels. For the last 50 years different physiological studies have shown that interstitial fluid drains from the brain along perivascular pathways into cervical lymphatics [2]. Using refined injection techniques and confocal microscopy, our group has demonstrated that drainage of interstitial fluid and solutes from the brain occurs along 100-150 nm-wide basement membranes in the walls of cerebral capillaries and arteries. Older experimental studies suggest that only 10-15% of solutes draining by this route escape into the CSF [3]. We have demonstrated that injection of soluble Aβ into the brain parenchyma of young mice results in its rapid elimination along the walls of capillaries and arteries [4]. Our theoretical modelling studies suggest that the motive force for perivascular lymphatic drainage is derived from vascular pulsations and biochemical interactions with basement membranes [5, 6]. With increasing age and arteriosclerosis, cerebral arteries become stiffer [7] and the amplitude of pulsations decreases. Motive force declines reducing efficiency of lymphatic drainage of the brain as shown in aged mice [4].

Our working hypothesis is that the deposition of amyloid plaques in the human brain with age and Alzheimer’s disease reflects a failure of elimination of Aβ from the brain. Several mechanisms for the elimination of Aβ from the brain have been defined. These include degradation by enzymes such as neprilysin [8], receptor-mediated absorption into the blood [9], passage into the CSF [10] and perivascular lymphatic drainage [11]. Reduction in neprilysin activity and failure of absorption of Aβ into the blood with age [8, 9] may divert more Aβ along perivascular lymphatic drainage pathways [8, 12]. 

As arteries age, lymphatic drainage becomes less efficient [4] and Aβ is deposited in basement membranes of arteries and capillaries as cerebral amyloid angiopathy (CAA), which further impairs perivascular lymphatic drainage [13]. APOE ε4 is also associated with impaired perivascular lymphatic drainage as demonstrated in mice expressing human ApoE ε4 [14].

As a result of the failure of elimination of Aβ from the brain associated with ageing of cerebral arteries and CAA there is loss of homoeostasis of the extracellular environment in the brain as reflected in the rise of soluble Aβ in Alzheimer’s disease [15]. It is likely that there is also failure of elimination of soluble metabolites other than Aβ adding further to the loss of homoeostasis of the neuronal environment. The association of CAA with accumulation of fluid in the subcortical white matter reported after recent therapeutic trials in Alzheimer’s disease suggests that drainage of fluid is ultimately impaired [16, 17].

We are working in an interdisciplinary manner to demonstrate that changes in extracellular matrix and artery walls due to age, genotype, diet or different patterns of innervation or branching of blood vessels could have a marked effect upon the extracellular environment of brain tissue leading especially to failure of elimination of Aβ from the extracellular space but also to failure of elimination of other metabolites and loss of homeostasis.  Our mission is to clarify the exact factors that are responsible for efficient drainage along basement membranes of capillaries and arteries in order to identify new therapeutic targets for cerebral amyloid angiopathy and Alzheimer’s disease.