The Role of the Neurovascular Unit in Maintaining Normal Blood-Brain Barrier Function and Healthy Ageing

Healthy ageing is an important goal in modern societies due to the demographic shift in the proportions of older people and the economic burdens associated with that. The brain vasculature is composed of highly specialised cells that form blood brain barrier (BBB) e.g. endothelial cells and pericytes, which play a critical role in maintaining normal brain function. The BBB also restricts the entry of many blood-borne molecules including toxins and inflammatory cells into the brain. However, there is now increased understanding that the structure and function of BBB is altered in many neurodegenerative diseases. Alterations to the BBB can have a direct effect on neuronal and synaptic functions through changes in blood flow, BBB permeability, nutrient supply, faulty clearance of toxic molecules and altered secretion of trophic factors. Interestingly, a recent clinical study demonstrated a strong association between pericyte loss, BBB disruption and cognitive impairment in humans. However, the field is still at the beginning of the journey to fully interrogate BBB alterations in ageing and their implications in neurodegenerative disorders. Based on the above, understanding how to preserve the cellular component and function of BBB through selective targeting approaches may represent a new therapeutic target to promote healthy ageing because of its critical role for normal brain function.
The aim of this project is to investigate the biological changes to key cellular and molecular components of the neurovascular unit (e.g endothelial cells and pericytes) during the ageing process that may compromise BBB function. We also aim to selectively target those regions with nanoparticles to preserve their function. The central hypothesis is that the communications between different component of the neurovascular unit are critical to maintain the neurovascular functions which are essential for normal brain performance. Our project aims to identify the underlying process during ageing that contribute to the loss of such communication and thus leads to progressive age-dependent vascular damage mediated by BBB disruption and entry of neurotoxic and inflammatory cells into the brain.

To test this, we propose to use normal aged rodents and accelerated ageing models such as SAMP8 mice and combine, at the later stages of the project, with inducible comorbidities such as peripheral inflammation and infection. We will use state-of-the art imaging techniques such as optical live imaging, in vivo multiphoton microscopy, SPECT/CT imaging, in vitro and in vivo markers of BBB permeability to study the structure and function of the neurovascular unit and the potential of selective targeting using nanoparticles.