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Bates, Jessica (2025) The effect of ageing on the blood-brain barrier: The potential of nanoparticle drug delivery systems to target cerebrovascular changes. PhD thesis, University of Nottingham, Nottingham Trent University.

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Abstract

Within physiological ageing, recent evidence has shown that alterations to blood-brain barrier (BBB) permeability are potentially caused by a shift towards non-selective entry of systemic molecules into the brain via transcytosis. The ability to exploit this to deliver therapeutic molecules to target age-related changes of the BBB via lipid nanoparticles is an area of particular interest.

In vivo C57BL/6 murine models were utlisied with ageing females ranging from 3-22 months in comparison to males at 3- and 18-months. Systemic inflammation was induced via lipopolysaccharide (LPS) in a separate cohort of 3- and 18-month females to investigate age-related neuroinflammatory responses. Mice were injected intravenously with fluorescently labelled lipid nanoparticles (DiI-lip) and other permeability markers such as albumin and dextran. Brain infiltration was then tracked post-injection using optical imaging and histological analysis, complemented with behavioural cognitive function tests. Neurovascular unit (NVU) components and pro-inflammatory cytokines were also assessed for changes during ageing to identify possible therapeutic targets. Anti-inflammatory interleukin-1 receptor antagonist (Il1-ra) was conjugated to liposomes to determine if inflammatory changes in physiological ageing were reduced.

Findings of the studies indicated that DiI-lip infiltration increased during ageing independent of sex but changes to NVU and transport mechanisms were regionally heterogenous. LPS-induced neuroinflammation did not cause significant changes to DiI-lip infiltration or NVU components but did increase adhesion molecule and cytokine expression in ageing mice. Proteomic results uncovered multiple protein expression changes when comparing aged mice to LPS mice. Reduction of adhesion molecules and microglial activation were found when aged mice were exposed to Il1-ra liposomes, but no changes were observed in BBB permeability or astrocytic activation.

Overall, this work highlights the potential of liposomes to deliver therapeutics through the aged BBB, but further work needs to be completed to understand the underlying transport mechanisms and translatability to the human environment.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Al-Ahmady, Zahraa Gibson, Claire
Keywords:	blood-brain permeability, liposomes, nanoparticles, drug delivery systems
Subjects:	Q Science > QP Physiology > QP351 Neurophysiology and neuropsychology R Medicine > RM Therapeutics. Pharmacology R Medicine > RS Pharmacy and materia medica
Faculties/Schools:	UK Campuses > Faculty of Science > School of Biosciences
Item ID:	80442
Depositing User:	Bates, Jessica
Date Deposited:	31 Jul 2025 04:40
Last Modified:	31 Jul 2025 04:40
URI:	https://eprints.nottingham.ac.uk/id/eprint/80442

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