Cholesterol Regulation in Age-Related Macular Degeneration: A Framework for Mathematical Modelling of Drusen Biogenesis
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Cholesterol Regulation in Age-Related Macular Degeneration: A Framework for Mathematical Modelling of Drusen Biogenesis Ronél Scheepers1,2 Robyn P. Araujo1,2
· Graeme J. Pettet1,2 · Peter van Heijster1 ·
Received: 26 November 2019 / Accepted: 25 September 2020 / Published online: 12 October 2020 © Society for Mathematical Biology 2020
Abstract In age-related macular degeneration (AMD), there is, in common with many other age-related diseases, the need to distinguish between changes in the ageing eye that lead to disease and those changes that are considered part of a healthy, ageing eye. Various studies investigating the multitude of mechanisms involved in the aetiology of AMD exist within the field of ophthalmology and related medical fields, yet many aspects of it remain poorly understood and only a limited number of therapies are available. A recent study relates drusen’s topographically cellular characteristics to the neural retina’s metabolic needs and associated cholesterol involvement within the retina. In particular, there is a need to fully understand the maintenance of cholesterol homeostasis in the retina to prevent normal ageing processes from being perturbed towards maculopathy. Here, we present an extensive review of the clinical and physiological features of the ageing retina, as well as mechanisms implicated in pathology, synthesised from a vast body of the published literature. We use this novel synthesis to construct a comprehensive process schematic, encompassing all key species and physiological processes such as nutrients, waste and lipoprotein management. We are therefore able to express these processes in a mathematical language via a comprehensive modelling framework, comprising a set of twenty-three equations spanning three distinct biological compartments. This very general modelling framework may now be adapted to more focused studies on individual mechanisms, processes or components underlying of the many facets of AMD. As an example of such a focused application, we conclude this article with a one-compartment, four-species model of the retinal pigment epithelium, which considers the parametric conditions under which either cholesterol homeostasis or unregulated accumulation of cholesterol may obtain in the ageing eye. Keywords Macula · AMD · Drusen · Cholesterol · Homeostasis · Mathematical modelling
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Abbreviations AROS Anti-reactive oxygen species AMD Age-related macular degeneration BLamD Basal laminar deposit BLinD Basal linear deposit BLL Bilipid layer BM Bruch’s membrane CC Choriocappilaris CC BL Choriocappilaris basal lamina CNV Choroidal neovascularisation DHA Docohexaenoate acid EC Esterified cholesterol ECM Extracellular matrix EL Elastin layer GA Geographic atrophy HDL High-density lipoprotein ICL Inner collagenous layer LDL Low-density lipoprotein LDL-R Low-density lipoprotein receptor LSC Light-sensitive cells nAMD Neovascular AMD NR Neural retina OCL Oute
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