Research
fluid clearance in the brain

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, cervical and dural 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 (BM) 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 BM of capillaries and arteries as intramural periarterial drainage (IPAD) (4).

Our theoretical modelling studies suggest that the motive force for perivascular lymphatic drainage is derived from vascular smooth muscle contractions and biochemical interactions with basement membranes (5) (6) (7). With increasing age and arteriosclerosis, cerebral arteries become stiffer (8) with reduced contractility of arterial smooth muscle cells. 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 (9), receptor-mediated absorption into the blood (10), passage into the CSF (11) and perivascular lymphatic drainage (12). Reduction in neprilysin activity and failure of absorption of Aβ into the blood with age (9) (10) may divert more Aβ along perivascular lymphatic drainage pathways (9) (13).

As arteries age, IPAD 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 (14). APOE ε4 is also associated with impaired perivascular lymphatic drainage as demonstrated in mice expressing human ApoE ε4 (15). 

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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 (16). 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 (17) (18).

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.  By clarifying the exact factors that are responsible for efficient drainage along basement membranes of capillaries and arteries we are in identifying new therapeutic targets for cerebral amyloid angiopathy and Alzheimer’s disease.

related projects

intramural cells as biomarkers and therapeutic targets for alzheimer’s disease

The aim is to firstly understand the roles and changes in the cerebrovascular intramural cells associated with the pathogenesis of CAA/AD, using novel in vivo models, post-mortem human tissue, ex vivo laser capture microdissection and cell culture microfluidic systems. Secondly, we will use a novel in vivo electrochemical ablation and therapeutic interventions to restore normal IPAD in models with depleted vascular mural cells. Thirdly, we will pilot new imaging and fluid biomarkers of human cerebrovascular mural cell health. This project promises to clarify the exact mechanism by which mural cells are the key players for IPAD, to identify new therapeutic targets in the form of adrenergic and cholinergic agents and novel imaging and fluid biomarkers that are sensitive and specific for the health of intramural cells and early detection of CAA/AD.

In collaboration with University of Medicine, Pharmacy, Science and Technology Targu Mures – Romania

TUBE: Transport Derived Ultrafines and their Brain Effects

 Dr Louise kelly

Air pollutants have been shown to cause a vast amount of different adverse health effects. These effects include the impairment of respiratory and cardiovascular function. However, in recent years, the evidence showing effects beyond the lung and circulatory system, has become more evident. Neurological diseases, namely Alzheimer’s disease (AD) has shown to be associated with living near traffic. Yet, the reason for this has remained unresolved. Despite the fact that air pollution and brain disease are linked, the effects of extremely fine particles on brain function have been insufficiently assessed. In addition, the molecular and cellular mechanisms underlying the connection between brain health, AD and air pollution remain completely unknown. While the association of air pollutants with cognitive decline and neurodegenerative diseases such as AD has been discussed, it has also remained unclear, which components of air pollution are responsible for these effects. Moreover, very little is known about the effects of extremely fine particles, as well as of (S)VOCs from combustion engines, especially regarding effects beyond the lung, the main entrance and primary target organ.

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There is an urgent need to understand the interplay of pollutants with adverse effects in the brain, in order to steer political decision making for efficient reduction of air pollutants. This could, in the long run, reduce the economic burden caused by diseases associated with them. To address this unmet need, the TUBE-project unites interdisciplinary expertise to study these adverse effects of extremely fine particles (UFP’s) in the human lung and brain. Leaning on this interdisciplinary approach and state of the art research methodologies, TUBE will aim to discover the harmful components of air pollution and identify biomarkers for early detection of brain disease realted to air pollution. This could improve brain health, reduce the prevalence of brain diseases, provide significant economical savings, and provide data that will be used to support planning future traffic policy across the EU.

Investigating Immunisation Strategies for the Treatment of Synucleinopathies

 Dr Christopher Brown

Next generation immunisation strategies have enabled the manufacture of highly efficacious vaccines to treat major global diseases which are currently untreatable. United Neuroscience (UNS), a biotechnological company, has aimed to overcome the current vaccine challenges in the field of neurodegenerative disease by designing highly targeted vaccines which elicit a protective immune response. Synucleinopathies comprise a group of neurodegenerative diseases that are characterised by primary alpha-synuclein (α-Syn) pathology such as Dementia with Lewy Bodies (DLB), Parkinson’s disease (PD) and Multiple systems atrophy (MSA). The central role of α-Syn in the pathogenesis of these diseases highlights it as a promising target for therapy. In this study we aim to test the effects of novel α-Syn vaccines developed by UNS on preventing the onset and progression of neurodegeneration in mouse models of these synucleinopathies. In order to investigate this, we first need to understand the pathway along which α-Syn is naturally cleared from the brain and we can then establish how immunotherapy modulates this process and evaluate the neuroprotective effects of this as a treatment.