Investigating the timing and causes of vascular dysfunction in Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder and leading cause of dementia. In addition to the main pathological hallmarks of AD, which include extracellular accumulation of amyloid beta (Aβ) plaques and intracellular accumulation of misfolded or hyperphosphorylated tau tangles, reduced blood flow and blood-brain barrier (BBB) leakiness are some of the earliest pathogenic features of AD. In brain regions such as precuneus, early changes in vascular function in AD development lead to reduced blood flow and impaired neurovascular coupling. In this study, I have explored the role and relationships between key neurovascular signalling pathways within the precuneus. I first outlined a method that I used to prepare highly enriched vessels samples and which showed alterations in vascular cell content, perivascular cell degeneration and decreased vessel diameter in AD. I next explored Angiopoietin/Tie (ANGPT/TIE) signalling in brain tissue, vessel-enriched samples, and CSF and showed that ANGPT/TIE signalling was dysregulated in AD as reflected by altered CSF levels of ANGPT/TIE signal proteins including ANGPT-2 and TIE-2. I also reported the association of alterations in ANGPT/TIE signalling with reduced tissue oxygenation and increased BBB leakiness in late-stage AD. Lastly, I have performed preliminary experiments in mono-cultures and 3D co-cultures of commercial human umbilical vascular endothelial cells (HUVEC) and human brain vascular pericytes (HBVP) exposed to Aβ at various concentrations that were incubated under normoxic or hypoxic conditions. Analysis showed that exposure to Aβ and hypoxia caused differential alterations in ANGPT/TIE signalling when HUVEC and HBVP were co-cultured.

Date of Award	9 Dec 2025
Original language	English
Awarding Institution	University of Bristol
Sponsors	Turkish Ministry of National Education
Supervisor	J S Miners (Supervisor) & Seth Love (Supervisor)