**1.2 Pathophysiology of AMD in humans**

Although incompletely understood, AMD is a complex disease that results from a mix of genetic predisposition, environmental factors, and age. There are many models that attempt to explain the pathophysiology of AMD, the underlying disease mechanisms of which are multifaceted and not mutually exclusive. These can be categorized as oxidative stress, inflammation, dysregulated antioxidants, lipid metabolism, and angiogenesis [13]. This chapter highlights the multifactorial etiology of RPE damage and dysfunction, a key event in AMD pathogenesis and briefly touches on other aspects of AMD pathophysiology [3].

A properly functioning RPE is important for retinal homeostasis because of the multiple roles it plays including: transportation of nutrients from the choroidal vasculature; absorption of stray photons of light; phagocytosis of photoreceptor outer segments; metabolism of fatty acids; formation of the blood-retinal barrier; regulation of subretinal water transport; and regeneration of visual pigments during the visual transduction cascade [14]. Some retinal changes that are characteristic of AMD include dysfunction of the RPE, sub-RPE deposition of lipids and proteins, neovascularization of the choroid or retina, and disciform scar formation [13]. Most people develop asymptomatic extracellular lipid deposition underneath the RPE. However, as these lesions enlarge they can cause dysfunction of the RPE [15]. Although an exact stepwise development of disease is not clear, early AMD is defined by the appearance of drusen under the RPE with thickening of Bruch's membrane (BrM). Consequently, this impairs the ability of the RPE to efflux fluids across BrM and to deliver nutrients such as glucose, vitamin A (all-*trans* retinal), and docosahexenoic acid (DHA), causing stress on the RPE and photoreceptors [15]. The impaired transport across BrM may exacerbate formation of drusen, thus causing a vicious cycle of pathology.

Moreover, the RPE is susceptible to oxidative stress from high oxygen utilization, prolonged exposure to visible light, lipid oxidation by photoreceptors and drusen, and cigarette smoking [4, 13]. During phototransduction, visual pigments called opsins use the chromophore 11-*cis* retinal to absorb photons of light. Upon absorption, the 11-*cis* configuration becomes all-*trans*, the initiating step for phototransduction. To convert the all-*trans* back to 11-*cis*, it must proceed through the retinoid cycle whereby the RPE re-isomerizes the molecule back to its 11-*cis* conformation. A byproduct of this cycle is A2E, which accumulates in lipofuscin — particularly in the macula — and reacts with oxygen to form free radicals. This may partly explain why the macula is preferentially affected in AMD [15]. Lipofuscin also accumulates in aging eyes which may exacerbate oxidative stress by forming free radicals and inhibiting the RPE's function of degrading organelles [4, 13]. In short, there are many etiologies of oxidative stress and the literature supports that it is an important part of AMD pathophysiology [13].

Identification of SNPs in several complement factor components sheds light on its role in AMD pathogenesis. The complement system is beneficial for its role in innate immunity and encouraging phagocytosis and removal of unwanted cellular material; however, dysregulation of this system can cause damage and inflammation in surrounding tissue [4]. Similarly, inflammation is a cascade of events that is beneficial in the short term in response to foreign and damaged material, yet chronic inflammation can be harmful and may contribute to the development of AMD [16]. There are many genetic variants of complement genes associated with AMD and one example is the Y402H polymorphism in the *CFH* gene. CFH normally regulates the alternate complement pathway by interfering with C3b and factor B interaction and inhibiting the formation of C3 convertase [17]. However, the

Y402H polymorphism prevents CFH from binding to BrM or to malondialdehyde, a byproduct of lipid peroxidation, ultimately causing unregulated complement activation and chronic inflammation [4, 13, 17].

Antioxidants scavenge reactive oxygen species (ROS) thereby attenuating oxidative stress. Nuclear factor erythyroid 2-related factor 2 (NRF2) is a transcription factor that upregulates antioxidants when signaled by oxidative stress. Studies of *Nrf2*−/− mice showed retinal damage and changes such as thickened BrM, sub-RPE deposits, and complement activation. Thus, antioxidants may protect against AMD, and in contrast, the loss of antioxidants, as shown in the *Nrf2*−/− mice, may exacerbate AMD progression [13].

In humans, the inner and outer retina are supplied by the retinal artery and choroidal circulation, respectively. The choroidal circulation is located beneath BrM, which acts as a physical barrier. Drusen accumulation may disrupt this barrier and when conditions favor angiogenesis, permeable blood vessels lacking endothelial tight junctions and pericytes can develop between the retina and choroidal blood vessels. These vessels can grow into the central retina, a process called choroidal neovascularization (CNV) as seen in exudative AMD [15, 18, 19]. Neovascularization may also originate from the retina in a process called retinal angiomatous proliferation (RAP) [17]. Vascular endothelial growth factor (VEGF) plays a major role in angiogenesis. There is sufficient evidence that points to the role of VEGF in exudative AMD pathogenesis, given the higher VEGF levels in AMD patients and the successful decrease in neovascularization with anti-VEGF agents [13]. Pigment epithelium-derived growth factor (PEDF) is an antiangiogenic molecule whose expression is reduced in eyes with AMD. This imbalance between angiogenic VEGF and antiangiogenic PEDF suggests that homeostasis of vascular factors is disrupted in exudative AMD [15]. In summary, AMD is a multifaceted disease with genetic and environmental risk factors that likely progresses due to a combination of oxidative stress and inflammation, combined with dysregulated antioxidants, lipid metabolism, and increased angiogenesis.

#### **1.3 Classification of AMD**

Disease classification can elucidate pathophysiological processes, prognosis, and guide in clinical decision-making. Drusen, the hallmark lesion of AMD, is visible by fundoscopy and can be classified by their size and border characteristics [15]. Specifically, drusen can be small (< 63 mm), intermediate (63–124 mm), or large (>124 mm). They can also be stratified as hard (well demarcated), soft (poorly demarcated), or confluent (contiguous) [20, 21]. Higher number and larger size of drusen portends greater likelihood of progression in AMD. Moreover, compared to hard drusen, soft drusen tend to be located in the macula and increase risk of progression [21].

AMD is categorized as non-exudative or exudative. There are many ways to stratify AMD, but this chapter uses the classification of the Age-Related Eye Disease Study (AREDS) as follows: no AMD (no or few small drusen), early AMD (multiple small drusen, few intermediate drusen, or mild RPE abnormalities), intermediate AMD (numerous intermediate drusen, at least one large drusen, or geographic atrophy without center foveal involvement), and advanced AMD (geographic atrophy with center foveal involvement or neovascular maculopathy) [22].

Each stage has defining characteristics. The advanced non-exudative form of AMD is known as geographic atrophy (GA) and is defined by slow progressive atrophy of the photoreceptors, RPE, and the choriocapillaris that form sharply demarcated lesions [23]. Advanced exudative AMD represents 10–15% of all AMD and is characterized by growth of choroidal blood vessels through BrM and into the *An Overview of Age-Related Macular Degeneration: Clinical, Pre-Clinical Animal Models… DOI: http://dx.doi.org/10.5772/intechopen.96601*

retina, consequently causing intraretinal or subretinal leakage, hemorrhage, and RPE detachment. These changes can cause acute vision loss [15, 18, 24]. Follow-up data from the AREDS found that progression to advanced AMD is associated with the following retinal risk factors: increased baseline drusen severity, the presence of a large drusen within 1 disc diameter of the fovea, the presence of bilateral medium drusen, the presence of advanced AMD in the fellow eye, and the simultaneous presence of AMD RPE abnormalities and large drusen [25].
