Abstract
Cardiovascular amyloidosis affects the health of a significant proportion of the global population. These diseases are characterised by the deposition of aggregates of misfolded protein called amyloid in the heart and vascular tissues. The commonly known conditions are cerebral amyloid angiopathy [CAA; a comorbidity in at least 40% of patients of Alzheimer’s disease (AD)], AL (deposition of immunoglobulin light chains), AA (deposition of serum amyloid A) and ATTR (transthyretin aggregation) amyloidoses. Over the past three decades, some more vascular diseases of the upper body, such as giant cell arteritis (GCA; the most common arterial inflammatory disease), thoracic aortic aneurysm (TAA) and dissection, and vascular dementia (VaD), have been added to the list due to the predominance of an amyloidogenic peptide called medin involved in their prognosis. Medin is one of the most common senile localised amyloids in humans, found in the aorta of almost all Europeans above the age of 60. It was first discovered in the tunica media of the aorta, the largest artery in humans and the main artery supplying oxygenated blood from the heart to the entire body. Medin is a 50-residue peptide formed by the enzymatic cleavage of the glycoprotein lactadherin which is involved in phagocytic clearance of apoptotic bodies. Medin aggregation affects vascular wall elasticity, vascular cell viability and inflammatory status. Medin colocalises with and enhances deposition of amyloid-β (Aβ) aggregates in the cerebral vasculature, which are linked with AD-type CAA. A correlation of cerebrovascular medin deposits with cognitive decline has suggested a potential role of medin aggregation in the disruption of the blood-brain barrier (BBB) in CAA. Despite its widespread occurrence in vascular pathology, medin biology suffers from a lack of a clear mechanistic description of medin aggregation, sparse information about how the human body regulates medin aggregation under physiological conditions, lack of in vitro and in vivo models of medin’s pathogenesis, irreproducibility in lab-based production protocols of medin for research purposes, and, hence, an absence of probes and clinical modulatory tools of medin pathogenesis. This thesis summarises a battery of approaches to address some of these gaps in the literature on medin. It reports: