PhD: Inhibition of complement activity in a model of Vascular Dementia

About the Project

Background

Vascular dementia is the second most common type of dementia after Alzheimer’s disease and is caused by impaired blood supply to the brain. A key causative factor in the pathogenesis of vascular dementia is the development of atherosclerosis affecting the small blood vessels within the brain. Other cardiovascular events such as strokes (large and small) are also major contributory events in the development of the disease. Common “lifestyle” risk factors affecting the development of vascular dementia are identical to those identified for cardiovascular disease and include: high blood pressure, high cholesterol, diabetes, obesity, physical inactivity and smoking.

We have previously shown that the complement system, a key component of innate immunity comprising more than 40 different proteins is intimately involved in the development and progression of atherosclerosis. Thus, in developing atherosclerotic plaques complement is activated, causing an inflammatory response that drives the disease. The absence of key complement proteins of the “terminal” pathway ameliorates disease (Lewis et al 2010). More recently we have focused on the mechanisms underlying the genetically proven links between complement and Alzheimer’s Disease (AD). Here again, we have demonstrated that therapeutic blockade of complement activation in a mouse model of AD through the administration of blocking antibodies can slow the development of the disease and improve cognitive performance (Zelek W.M. et al 2024).

Modelling Dementia in animals relies largely on genetically altered mice carrying the human transgenes responsible for familial AD. This is not ideal since familial AD comprises only a small percentage of dementia cases. Recent publications have described, more relevant models to address the pathology of vascular dementia (Sweetat S. et al 2024, Kruyer A. et al 2015). Given the vascular damage and inflammation that has been documented in these new models we hypothesise that complement will be activated and play a significant contributory role in driving disease.

Aims

To test our hypothesis, we shall use the published ovariectomised model of vascular dementia where female mice are fed a diet high in fat, sugar and salt to mimic post-menopausal ageing together with several of the key risk factors relevant to human vascular dementia. The model will be used in three sets of experimental analyses:

1) We shall assess the extent of complement activation in these model mice. This will be carried out through the use of in-house ELISA-based assays and immunohistochemistry in the serum and brain tissues of these animals respectively.

2) We shall utilise in-house complement deficient strains (eg C7-/-; C3-/- and CD59) to understand the effect of deleting key complement genes in this model of vascular dementia.

3) We shall administer our previously validated anti-complement antibodies (anti C7) to determine whether complement blockade is a viable therapeutic approach to vascular dementia in this model.

Methodologies Employed

A range of techniques will be employed throughout this project to assess disease and test the effectiveness of our therapeutic approach. Thus, ELISA based assays, behavioural tests and immunohistochemistry staining for a range of markers in the brain tissues of these mice including (C3b; MAC; amyloid; tau; Iba-1; GFAP) will be utilised in all three aims. These will validate the model in our hands and allow assessment of the activation of complement. Furthermore, In the serum of model animals, Cytokines, Cholesterol, triglycerides, glucose and liver enzyme function will be assessed at baseline, during and at the end of each experiment. Where needed we shall confirm these findings by ELISA based analyses of total brain homogenates. RNA will be isolated and used in qPCR assessment of specific gene sets relevant to vascular dementia, neuroinflammation and complement. Supporting methodologies will include cell culture, protein purification and complement haemolysis assays to produce, purify and test the therapeutic antibodies that we will employ.

Potential Impact

This project will establish the extent of complement activation and its role in driving the progression of vascular dementia in a newly emerging relevant model of the vascular dementia. Data obtained will allow an assessment of the efficacy of inhibiting complement during the disease as a therapeutic approach. These outcomes could have important implications for how the second most common form of dementia is measured, and open new directions for therapeutic development.

How to apply:

Please use our online application service at: https://www.cardiff.ac.uk/study/postgraduate/research/programmes/programme/pharmacy

and specify in the funding section that you wish to be considered for WHRI funding.

Please also specify the project title and supervisor

The closing date for applications is 6th March 2026 and we expect interviews to be held in April

The successful applicant is likely to have a very good first degree (a First or Upper Second class Honours or equivalent)

Key details

• Location UK DRI at Cardiff
• Salary: This Wales Heart Research Institute Cardiovascular Fund studentship is open to Home and EU applicants. The award offered will cover fees and a maintenance stipend (for 26/27 this will be approx. £21,300).