Development of vascularised human brain cell co-cultures to improve translation in Alzheimer's disease drug discovery

Abstract

Alzheimer’s disease (AD) is a complex neurodegenerative disorder marked by cognitive decline, amyloid β (Aβ) and tau pathology, neuroinflammation, and neurovascular dysfunction. Despite increasing recognition of the neurovascular unit’s role in AD, current models rely on simplistic 2D monocultures and animal systems that inadequately recapitulate human neurovascular complexity, limiting their translational value. This thesis addresses these limitations by 3D bioprinting induced pluripotent stem cell-derived neurovascular cells to develop physiologically relevant, scalable neurovascular models.

In Chapter 3, we differentiated and characterised iPSC-derived brain microvascular endothelial-like cells (iBMECs) and pericytes. iBMECs exhibited superior barrier function compared to primary and immortalised alternatives, while iPericytes displayed distinct inflammatory and vascular maintenance profiles. In Chapter 4, we optimised media composition to enable robust 3D bioprinting of iBMECs and developed multicellular tricultures that reflect in vivo neurovascular architecture. Chapter 5 applies these systems to investigate endothelial responses to Aβ40, Aβ42, and inflammatory stimuli (including E. coli and P. gingivalis LPS). Findings reveal in vivo-like Aβ deposition and altered VE-cadherin expression, suggesting complex interactions between neuroinflammation and Aβ in modulating barrier function.

Collectively, this thesis establishes a novel 3D iPSC-based neurovascular platform for mechanistic interrogation of AD pathology, with strong potential for adaptation to high-throughput drug discovery.