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Cholesterol Regulation in Age-Related Macular Degeneration: A Framework for Mathematical Modelling of Drusen Biogenesis

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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.

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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:

Outer collagenous layer

POS:

Photoreceptor outer segments

PR:

Photoreceptors

RPE:

Retinal pigment epithelium

RPE BL:

Retinal pigment epithelium basal lamina

ROS:

Reactive oxygen species

SDD:

Subretinal drusenoid deposit

TG:

Triglycerides

UC:

Unesterified cholesterol

VEGF:

Vascular endothelial growth factor

VLDL:

Very low-density lipoprotein

TGF-\(\beta \) :

Transforming growth factor beta

TIMP-3:

Tissue inhibitor of metalloproteinase-3

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Acknowledgements

Robyn P. Araujo is the recipient of an Australian Research Council (ARC) Future Fellowship (project number FT190100645) funded by the Australian Government.

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  1. School of Mathematical Sciences, Queensland University of Technology, Brisbane, Qld, 4000, Australia

    Ronél Scheepers, Graeme J. Pettet, Peter van Heijster & Robyn P. Araujo

  2. Institute of Health and Biomedical Innovation (IHBI), 60 Musk Avenue, Kelvin Grove, Qld, 4059, Australia

    Ronél Scheepers, Graeme J. Pettet & Robyn P. Araujo

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Scheepers, R., Pettet, G.J., van Heijster, P. et al. Cholesterol Regulation in Age-Related Macular Degeneration: A Framework for Mathematical Modelling of Drusen Biogenesis. Bull Math Biol 82, 135 (2020). https://doi.org/10.1007/s11538-020-00812-0

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