What is IPAD?

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).

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

IPAD in neurodegenerative disease

Investigating Immunisation Strategies for the Treatment of Synucleinopathies

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.

Key researcher

Jacqui Nimmo

PHD STUDENT

  • jtn1g13@soton.ac.uk

Output

Amyloid-β and α-Synuclein Immunotherapy: From Experimental Studies to Clinical Trials. Nimmo, JT, Kelly, L, Verma, A, Carare, RO, Nicoll, JAR et al.. Front Neurosci. 2021;15 :733857. doi: 10.3389/fnins.2021.733857. PubMed PMID:34539340 PubMed Central PMC8441015.

Novel antibodies detect additional α-synuclein pathology in synucleinopathies: potential development for immunotherapy. Nimmo, JT, Verma, A, Dodart, JC, Wang, CY, Savistchenko, J et al.. Alzheimers Res Ther. 2020;12 (1):159. doi: 10.1186/s13195-020-00727-x. PubMed PMID:33256825 PubMed Central PMC7702704.

The Pattern of AQP4 Expression in the Ageing Human Brain and in Cerebral Amyloid Angiopathy. Owasil, R, O'Neill, R, Keable, A, Nimmo, J, MacGregor Sharp, M et al.. Int J Mol Sci. 2020;21 (4):. doi: 10.3390/ijms21041225. PubMed PMID:32059400 PubMed Central PMC7072949.

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Output

Novel antibodies detect additional α-synuclein pathology in synucleinopathies: potential development for immunotherapy. Nimmo, JT, Verma, A, Dodart, JC, Wang, CY, Savistchenko, J et al.. Alzheimers Res Ther. 2020;12 (1):159. doi: 10.1186/s13195-020-00727-x. PubMed PMID:33256825 PubMed Central PMC7702704.

Funding

United Neuroscience project grant – “New immunisation strategies for Alzheimer’s disease“. £250,000

Medical Research Council UK & United Neurosciences  “Investigating immunisation strategies for the treatment of alpha synucleinopathies“.  £70,000

IPAD in neurodegenerative disease

Failure of drainage of fluid from the brain along the walls of blood vessels in vascular dementia

Cerebral small vessel disease (SVD) is a key feature of vascular dementia, radiologically defined by the presence of white matter hyperintensities, lacunar infarcts, microbleeds and perivascular spaces.  Cerebral arteriolosclerosis resulting in loss of elasticity and segmental disorganisation of the arterial wall leads to damage of the deep white matter.  The primary functions of penetrating and perforating cerebral arteries supplying blood and drainage of fluid and solutes from the parenchyma along IPAD pathways are impaired.  In this project, using animal models and post-mortem brain tissue from stroke survivors with SVD (CogFAST study) along with light sheet 3D microscopy and post-mortem MRI, we will assess the immunocytochemical pattern of distribution of AQP4, α-dystrobrevin and β-dystroglycan.  We will then test the hypotheses that 1) disruption in the anchoring system of the basement membranes such as that observed in α-dystrobrevin knock-out mice and 2) disruption of gliovascular end feet tracked by aquaporin 4 (AQP4) knock-out mice there is failure of perivascular clearance of fluid from the deep gray matter and the corpus callosum.  Our aim is to demonstrate that failure of perivascular drainage of fluid from the brain is a mechanism underlying SVD and this could be targeted therapeutically.

Key researcher

Dr Matt MacGregor Sharp

POSTDOCTORAL FELLOW

  • m.t.sharp@soton.ac.uk

Output

Vascular α1A Adrenergic Receptors as a Potential Therapeutic Target for IPAD in Alzheimer's Disease. Frost, M, Keable, A, Baseley, D, Sealy, A, Andreea Zbarcea, D et al.. Pharmaceuticals (Basel). 2020;13 (9):. doi: 10.3390/ph13090261. PubMed PMID:32971843 PubMed Central PMC7560129.

Demonstrating a reduced capacity for removal of fluid from cerebral white matter and hypoxia in areas of white matter hyperintensity associated with age and dementia. MacGregor Sharp, M, Saito, S, Keable, A, Gatherer, M, Aldea, R et al.. Acta Neuropathol Commun. 2020;8 (1):131. doi: 10.1186/s40478-020-01009-1. PubMed PMID:32771063 PubMed Central PMC7414710.

ApoE4 Astrocytes Secrete Basement Membranes Rich in Fibronectin and Poor in Laminin Compared to ApoE3 Astrocytes. Keable, A, O'Neill, R, MacGregor Sharp, M, Gatherer, M, Yuen, HM et al.. Int J Mol Sci. 2020;21 (12):. doi: 10.3390/ijms21124371. PubMed PMID:32575521 PubMed Central PMC7352194.

The Pattern of AQP4 Expression in the Ageing Human Brain and in Cerebral Amyloid Angiopathy. Owasil, R, O'Neill, R, Keable, A, Nimmo, J, MacGregor Sharp, M et al.. Int J Mol Sci. 2020;21 (4):. doi: 10.3390/ijms21041225. PubMed PMID:32059400 PubMed Central PMC7072949.

Solving an Old Dogma: Is it an Arteriole or a Venule?. MacGregor Sharp, M, Criswell, TP, Dobson, H, Finucane, C, Verma, A et al.. Front Aging Neurosci. 2019;11 :289. doi: 10.3389/fnagi.2019.00289. PubMed PMID:31695607 PubMed Central PMC6817770.

Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways. Albargothy, NJ, Johnston, DA, MacGregor-Sharp, M, Weller, RO, Verma, A et al.. Acta Neuropathol. 2018;136 (1):139-152. doi: 10.1007/s00401-018-1862-7. PubMed PMID:29754206 PubMed Central PMC6015107.

The fine anatomy of the perivascular compartment in the human brain: relevance to dilated perivascular spaces in cerebral amyloid angiopathy. MacGregor Sharp, M, Bulters, D, Brandner, S, Holton, J, Verma, A et al.. Neuropathol Appl Neurobiol. 2019;45 (3):305-308. doi: 10.1111/nan.12480. PubMed PMID:29486067 .

The meninges as barriers and facilitators for the movement of fluid, cells and pathogens related to the rodent and human CNS. Weller, RO, Sharp, MM, Christodoulides, M, Carare, RO, Møllgård, K et al.. Acta Neuropathol. 2018;135 (3):363-385. doi: 10.1007/s00401-018-1809-z. PubMed PMID:29368214 .

The perivascular pathways for influx of cerebrospinal fluid are most efficient in the midbrain. Dobson, H, Sharp, MM, Cumpsty, R, Criswell, TP, Wellman, T et al.. Clin Sci (Lond). 2017;131 (22):2745-2752. doi: 10.1042/CS20171265. PubMed PMID:29021222 .

The structure of the perivascular compartment in the old canine brain: a case study. Criswell, TP, Sharp, MM, Dobson, H, Finucane, C, Weller, RO et al.. Clin Sci (Lond). 2017;131 (22):2737-2744. doi: 10.1042/CS20171278. PubMed PMID:28982724 .

Arterial Pulsations cannot Drive Intramural Periarterial Drainage: Significance for Aβ Drainage. Diem, AK, MacGregor Sharp, M, Gatherer, M, Bressloff, NW, Carare, RO et al.. Front Neurosci. 2017;11 :475. doi: 10.3389/fnins.2017.00475. PubMed PMID:28883786 PubMed Central PMC5574214.

Vascular basement membrane alterations and β-amyloid accumulations in an animal model of cerebral small vessel disease. Held, F, Morris, AWJ, Pirici, D, Niklass, S, Sharp, MMG et al.. Clin Sci (Lond). 2017;131 (10):1001-1013. doi: 10.1042/CS20170004. PubMed PMID:28348005 .

Quantitative Assessment of Cerebral Basement Membranes Using Electron Microscopy. Sharp, MM, Page, A, Morris, A, Weller, RO, Carare, RO et al.. Methods Mol Biol. 2017;1559 :367-375. doi: 10.1007/978-1-4939-6786-5_25. PubMed PMID:28063057 .

Investigating the Lymphatic Drainage of the Brain: Essential Skills and Tools. Albargothy, NJ, Sharp, MM, Gatherer, M, Morris, A, Weller, RO et al.. Methods Mol Biol. 2017;1559 :343-365. doi: 10.1007/978-1-4939-6786-5_24. PubMed PMID:28063056 .

Vascular basement membranes as pathways for the passage of fluid into and out of the brain. Morris, AW, Sharp, MM, Albargothy, NJ, Fernandes, R, Hawkes, CA et al.. Acta Neuropathol. 2016;131 (5):725-36. doi: 10.1007/s00401-016-1555-z. PubMed PMID:26975356 PubMed Central PMC4835509.

Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid-β from the mouse brain. Hawkes, CA, Gatherer, M, Sharp, MM, Dorr, A, Yuen, HM et al.. Aging Cell. 2013;12 (2):224-36. doi: 10.1111/acel.12045. PubMed PMID:23413811 .

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Output

Demonstrating a reduced capacity for removal of fluid from cerebral white matter and hypoxia in areas of white matter hyperintensity associated with age and dementia. MacGregor Sharp, M, Saito, S, Keable, A, Gatherer, M, Aldea, R et al.. Acta Neuropathol Commun. 2020;8 (1):131. doi: 10.1186/s40478-020-01009-1. PubMed PMID:32771063 PubMed Central PMC7414710.

Funding

Stroke Association Priority Programme Award (vascular dementia) – “Failure of drainage of fluid from the brain along the walls of blood vessels in vascular dementia“. £245,198.00

IPAD in neurodegenerative disease

TUBE: Transport Derived Ultrafines and their Brain Effects

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.

Key researcher

Dr Louise Kelly

POSTDOCTORAL FELLOW

  • l.kelly@soton.ac.uk

Output

Amyloid-β and α-Synuclein Immunotherapy: From Experimental Studies to Clinical Trials. Nimmo, JT, Kelly, L, Verma, A, Carare, RO, Nicoll, JAR et al.. Front Neurosci. 2021;15 :733857. doi: 10.3389/fnins.2021.733857. PubMed PMID:34539340 PubMed Central PMC8441015.

Identification of intraneuronal amyloid beta oligomers in locus coeruleus neurons of Alzheimer's patients and their potential impact on inhibitory neurotransmitter receptors and neuronal excitability. Kelly, L, Seifi, M, Ma, R, Mitchell, SJ, Rudolph, U et al.. Neuropathol Appl Neurobiol. 2021;47 (4):488-505. doi: 10.1111/nan.12674. PubMed PMID:33119191 .

The Pattern of AQP4 Expression in the Ageing Human Brain and in Cerebral Amyloid Angiopathy. Owasil, R, O'Neill, R, Keable, A, Nimmo, J, MacGregor Sharp, M et al.. Int J Mol Sci. 2020;21 (4):. doi: 10.3390/ijms21041225. PubMed PMID:32059400 PubMed Central PMC7072949.

Brain pharmacology of intrathecal antisense oligonucleotides revealed through multimodal imaging. Mazur, C, Powers, B, Zasadny, K, Sullivan, JM, Dimant, H et al.. JCI Insight. 2019;4 (20):. doi: 10.1172/jci.insight.129240. PubMed PMID:31619586 PubMed Central PMC6824309.

Dynamic Modulation of Mouse Locus Coeruleus Neurons by Vasopressin 1a and 1b Receptors. Campos-Lira, E, Kelly, L, Seifi, M, Jackson, T, Giesecke, T et al.. Front Neurosci. 2018;12 :919. doi: 10.3389/fnins.2018.00919. PubMed PMID:30618551 PubMed Central PMC6295453.

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Funding

Horizon 2020 TUBE-LC-MG-2018 – “Transport derived ultrafines and their brain effects“. £239,039     More info