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Title: Perivascular pathways for the elimination of soluble and particulate matter from the brain : significance for Alzheimer's disease and neuroimmunology
Author: Carare-Nnadi, Roxana Octavia
ISNI:       0000 0001 3519 4333
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2006
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This thesis focuses upon defining the exact pathways by which soluble tracers and insoluble particulate mater are eliminated from the grey matter of the mouse brain along the walls of cerebral capillaries and arteries. I test the major hypothesis that solutes and particles are eliminated from the brain along the same perivascular bulk flow pathways and their drainage is unaffected by inflammation. Four major sets of experiments were performed, with the following results: (1) When injected into the mouse brain, 0.02μm fluorospheres (but not 1μm fluorospheres) entered perivascular spaces around arteries and capillaries but reached cervical lymph nodes only after injection into the CSF. The distribution was the same at all timepoints. (2) Soluble dextran spread diffusively through the extracellular spaces of grey matter in the mouse brain and within 5 minutes was distributed within basement membranes of capillary walls and the media of arteries. At 3 hours, and more extensively at 24 hours, the soluble tracer formed punctuate deposits within perivascular cells. Following coinjection with LPS and kainic acid, soluble and insoluble tracers showed a wider distribution at 24 hours, but did not reach cervical lymph nodes. (3) Laminin in vascular basement membranes decreases with age. (4) Soluble Aβ does not bind to laminin in vitro. The results of this study have shown that solutes and particles are eliminated along different perivascular bulk flow pathways and drainage is modified by inflammation. The significance of this study for neuroimmunology is that perivascular pathways exist for drainage of soluble antigens, but there does not seem to be a pathway for the periarterial migration of inflammatory cells from the brain. Soluble tracer and, by extension, peptides such as Aβ appear to drain from the brain along perivascular interstitial fluid drainage pathways. In AD failure of perivascular drainage may be a factor in the accumulation of Aβ in capillary and arterial basement membranes as cerebral amyloid angiopathy. The working hypothesis arising from the work in this thesis is that age changes in artery walls impede the elimination of Aβ and ISF from the brain. Results in this thesis will form the basis of work towards new therapeutic strategies that will target the dynamics of ISF drainage pathways.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available