REVIEW Open AccessUnderstanding AMD by analogy: systematicreview of lipid-related common pathogenicmechanisms in AMD, AD, AS and GNQinyuan Xu, Sijia Cao, Sanjeeva Rajapakse and Joanne A. Matsubara*AbstractRationale: Age-related macular degeneration (AMD) is one of the leading causes of blindness among the elderly.Due to its complex etiology, current treatments have been insufficient. Previous studies reveal three systems closelyinvolved in AMD pathogenesis: lipid metabolism, oxidation and inflammation. These systems are also involved inAlzheimer’s disease, atherosclerosis and glomerulonephritis. Understanding commonalities of these four diseasesmay provide insight into AMD etiology.Objectives: To understand AMD pathogenesis by analogy and suggest ideas for future research, this study summarizesmain commonalities in disease pathogenesis of AMD, Alzheimer’s disease, atherosclerosis and glomerulonephritis.Methods: Articles were identified through PubMed, Ovid Medline and Google Scholar. We summarized the commonfindings and synthesized critical differences.Results: Oxidation, lipid deposition, complement activation, and macrophage recruitment are involved in all four diseasesshown by genetic, molecular, animal and human studies. Shared genetic variations further strengthen their connection.Potential areas for future research are suggested throughout the review.Conclusions: The four diseases share many steps of an overall framework of pathogenesis. Various oxidative sourcescause oxidative stress. Oxidized lipids and related molecules accumulate and lead to complement activation, macrophagerecruitment and pathology. Investigations that arise under this structure may aid us to better understand AMD pathology.Keywords: Lipids/oxidation, Cholesterol, Apolipoproteins, Inflammation, Complement, Macrophages, DiseasesBackgroundAge-related macular degeneration (AMD) has becomethe third leading cause of blindness within developedcountries and among the elderly, ranked after cataractand glaucoma [1]. Due to its complex etiology, currenttherapeutic approaches have been insufficient at treatingearly AMD. Previous studies of AMD reveal three sys-tems that are closely associated with its pathogenesis:lipid metabolism, oxidative stress and the inflammatoryprocess. Interestingly, these same three systems are alsoinvolved in Alzheimer’s disease (AD), atherosclerosis(AS) and glomerulonephritis (GN). In addition, generalrisk factors such as advanced age, smoking and specificgenetic variations are shared between AMD and thesethree diseases [2–6]. Most importantly, each disease haslipid-rich deposits that are characteristic of their path-ology. Together, these commonalities lead us to investi-gate the shared pathogenic mechanisms among the fourdiseases, which may provide insight into those aspects ofAMD development that are still unclear. The scope ofthis paper includes deposition of lipids and lipoproteinsand their consequences in the four diseases.Age-related macular degenerationAge-related macular degeneration (AMD) has quicklybecome the leading cause of vision impairment forthe elderly in developed countries. While early andintermediate AMD do not usually cause symptoms,late AMD can cause severe central vision loss. LateAMD affects the macular region on the retina and isdivided broadly into two types. Nonexudative (dry)* Correspondence: jms@mail.ubc.caDepartment of Ophthalmology and Visual Sciences, Faculty of Medicine,University of British Columbia, Vancouver, BC V5Z 3N9, Canada© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Xu et al. Lipids in Health and Disease (2018) 17:3 DOI 10.1186/s12944-017-0647-7AMD is characterized by drusen, a type of lipid-richextracellular deposit. Advanced nonexudative AMD,called geographic atrophy, involves a slow deterior-ation of the retinal pigment epithelium (RPE) andsecondary photoreceptor loss. Exudative (wet) AMDis characterized by choroidal neovascularization. Al-though this form of AMD is less common than non-exudative AMD, its onset is more acute and causes90% of all cases of severe vision loss due to AMD.Currently, there are no treatments for early AMDand its etiology has yet to be fully characterized. Amultitude of risk factors have been recognized. Aging,smoking and genetic predisposition are found to becommon amongst AMD patients [3, 7, 8]. Patho-logical processes such as lipid metabolism, oxidativestress and inflammation are suggested to be closelyinvolved in AMD pathogenesis. Recently, Pujol-Lereisand colleagues suggested a reasonable pathogenicmechanism that links the three systems [9]. Underoxidative stress, lipid deposits called drusen form inthe retina and trigger chronic inflammation by acti-vating the complement system. Then, immune cellssuch as macrophages facilitate more severe pathogen-esis. These events eventually cause RPE cell deathand central vision loss.Alzheimer’s diseaseAlzheimer’s disease (AD) is a progressive neurodegener-ative disease and the most common form of dementia inolder adults. Clinically, AD patients first develop an in-ability to form recent memories, which then progressesto a stage of dementia that affects all cognitive functions.Later in the disease course, AD patients commonly relyon caregivers for basic activities of daily living, and manyhave shortened life spans. Clinical examination, lumbarpuncture or PET imaging studies can diagnose AD, al-though each has its own drawbacks such as specificity oraccessibility. Brain structures such as the hippocampusand cerebral cortex are involved, resulting in progressiveinability to consolidate memories and perform higherfunctions such as decision making. Pathologically, hall-marks of AD include intracellular neurofibrillary tanglesand extracellular amyloid-β (Aβ) protein plaques, ac-companied by reactive microgliosis, dystrophic dendritesand axons, loss of synapses and neuronal degeneration[10]. It has been widely reported that lipid homeostasisaround cholesterol, oxysterol and apolipoproteins arealso crucially involved in AD pathogenesis [11, 12].AtherosclerosisAtherosclerosis (AS) is a degenerative process thatinvolves inflammatory lesions of the arterial walls. It canaffect larger blood vessels such as the carotid artery orsmaller vessels such as the coronary artery. Dependingon the type of blood vessels involved, it increases therisk of stroke and cardiovascular diseases such as myo-cardial infarction. While the incidence of stroke hasdeclined globally, the incidence of AS-related heart dis-ease increased particularly in Eastern Europe and Asia[13]. Apart from ischemic brain and heart disease, AScan also affect the peripheral vascular system resultingin claudication, or gastrointestinal vascular system. Somemay have severe consequences such as ruptured abdom-inal aortic aneurysms. Diet, smoking, exercise andgenetic risk factors have been identified for AS and othercardiovascular diseases. In AS, lipoproteins and lipidscross endothelium of large arteries and deposit in thearterial intima. Eventually these deposits form athero-sclerotic plaques inside the arteries and cause furtherdamage to the cardiovascular system by inducingchronic inflammation [14].GlomerulonephritisGlomerulonephritis (GN) is a term used to describethe group of diseases affecting glomeruli in the kid-neys. There are many subtypes of GN. This paper willfocus primarily on Type II membranoproliferativeglomerulonephritis (MPGN II), with a brief mentionof relevant studies in other GN subtypes. AlthoughMPGN is an uncommon cause of chronic nephriticdisease, literature supports that MPGN is a globalphenomenon. It has been reported to be a commonform of primary glomerular disease in Peru and Af-rica [15, 16]. In the US and Japan, many cases ofMPGN are associated with chronic hepatitis C virusinfection [17, 18]. Interestingly, epidemiology ofMPGN is variable throughout different parts of theworld, likely due to differences in genetics as well asenvironmental exposure. Clinically, MPGN results insevere proteinuria and end-stage renal disease. MPGNmay be idiopathic or a secondary manifestation of asystemic disease. The idiopathic MPGNs are furtherdivided into three subtypes. Type I is characterized bysubendothelial deposits, type II is characterized bydense deposits in the glomerular basement membraneand type III is characterized by subepithelial and sub-endothelial deposits. Major pathological events inMPGN II include the presence of a hypercellular kid-ney mesangium and electron dense material accumu-lating in the glomerular basement membrane. Lipiddysregulation in the kidneys has been used as analogyto study and understand other diseases such as ASand systemic AA amyloidosis [19, 20]. The lipidnephrotoxicity hypothesis suggests that kidney dis-eases involve many of the similar processes in AMD.These include problems in lipid transport, which thenleads to lipid relocation and accumulation in differentdiseased tissues [19].Xu et al. Lipids in Health and Disease (2018) 17:3 Page 2 of 13Oxidation and lipid-rich depositsOxidative stressAMD, AD, AS and GN are lipid-related diseases inwhich extracellular lipid-rich deposits, lipid-related pro-teins, and oxidized lipids play a pathological role. Thesource of oxidation varies between the four diseases.Photo-oxidation is uniquely applicable to eye diseases.Previous studies correlate high exposure to sunlight orUV light to the development of AMD [21, 22]. Reactiveoxygen species (ROS) related oxidative processes happenthroughout the body, but more prone to the eyes, thebrain and the kidneys. These organs are known to havehigh and constant blood supply, which exposes them tohigh oxygen partial pressures that increase the likelihoodof ROS production. In AMD, with the highly oxidativeenvironment in the retina, ROS is produced in the RPEcells [23]. It is also widely understood that ROS cancause lipid peroxidation and serves as an important in-ducer of AS development [24]. In vitro experimentsusing human endothelial cells confirmed the existence ofproatherosclerotic oxidative stress from ROS producedby NADPH oxidase [25]. Since chemical exposure fromcigarette smoking is an important risk factor for bothAMD and AS, and currently it is unknown whether theoxidants in cigarettes reaches the eye, furtherinvestigation should be done to see if cigarette smokingresult in excessive ROS production in the eyes. Certaintoxin-related oxidation is uniquely involved in AD. Ithas been reported that pathologic protein aggregatessuch as Aβ peptide, α-synuclein, and tau-441 proteininduce oxidative stress and over production of ROS[26, 27]. Following this framework of toxin inducedROS production in AD pathology, combined with theobservation that very low density-like lipoproteins(VLDL) are produced and secreted by RPE [28], it isreasonable to next investigate whether VLDLs induceROS formation in RPE. To our best knowledge, oxi-dative stress in MPGN II is not well studied, but oxi-dative stress plays an important role in kidneydamage. In human renal glomerular endothelial cells,advanced oxidation protein products induce endoplas-mic reticulum stress and endothelial-to-mesenchymaltransition [29]. In a transgenic mouse model of focalsegmental glomerular sclerosis, renal podocytessecreted endothelin-1, which induced mitochondrialoxidative stress in renal endothelial cells [30]. Inter-estingly, plant extract from Cordyceps militarisreduced oxidative stress and inflammation by normal-izing nuclear factor kappa B activity. This resulted inrecovery of kidney function and histological architec-ture in a rat model of membranous glomeruloneph-ritis, a subtype of GN related to MPGN [31]. Thesestudies suggest an important role of oxidative stressin MPGN and related pathologies.Lipid-rich depositsIn addition to oxidative stress, accumulation of lipid-relatedmolecules is another common factor seen in AMD, AD, ASand GN. Along with other molecules, oxidized lipids andlipid-related molecules accumulate in the Bruch’s mem-brane (BrM) of retina, brain parenchyma, arterial intima,and glomerular basement membrane (GBM).The deposits found in the retina are called drusen, anextracellular deposit rich in lipid and protein [32]. In2010, Wang et al. reported that more than 40% of dru-sen volume is composed of lipid-containing particles[32]. There are several types of drusen with differentmorphology and contents [33]. Soft drusen havehomogenous content and exist in the macula region,while hard drusen have substructures and appear in bothmacular and peripheral regions [33, 34]. Other types ofclinically detectable drusen include cuticular drusen, cal-cified drusen, reticular pseudodrusen and “ghost drusen”[34]. For a comprehensive review of the different typesof drusen, please refer to [34]. The exact mechanism ofdrusen formation remains unclear to this day, but theor-ies exist for the process of cell damage due to lipid de-position. Preceding drusen formation, BrM thickens dueto accumulation of lipids, heterogeneous material andinflammatory debris, which slows down nutrient andwaste transportation between RPE cells and capillarylamina of choroid, leading to RPE cell damage [35]. Re-cently, Thompson et al. proposed a novel mechanism ofdrusen biogenesis based on hydroxyapatite spherules[36]. First, natural lipid droplets form at the RPE/chor-oid interface. Then, insoluble hydroxyapatite shells formaround them. Finally, proteins and lipids attach to hy-droxyapatites and initiate drusen formation [36].Lipid-rich deposits like drusen are found in the otherthree diseases as well. In AD, the deposits found in thebrain parenchyma are called senile plaques (SP). SPs areround masses in the brain composed of amyloid peptides,oxidized proteins and lipids. In AS, atherosclerotic plaquesare formed when lipids cross the blood endothelium intothe intima of the arteries. Since the 1990s, it has beenestablished that atherosclerotic plaques contain oxidizedlipids, as well as other components such as tocopheroland ascorbate [37]. The deposits formed in MPGN areelectron dense deposits that sit in the GBM and are diag-nostic of MPGN II [38]. While the exact composition ofthe electron dense deposits remains unclear, they are dis-tinctively different from normal GBM under histologicalexamination [39]. Interestingly, patients with MPGN IIalso develop ocular lesions that are indistinguishable fromAMD [40]. Given this important commonality of lipid-rich depositions between the four diseases, future studiesshould pay attention to the compositions of these depositsin order to find worthwhile therapeutic targets commonto multiple diseases.Xu et al. Lipids in Health and Disease (2018) 17:3 Page 3 of 13Lipid-related moleculesAlthough there are many lipid-related molecules in-volved in the pathogenesis of AMD, AD, AS and GN,not all of them are involved in oxidation. Some of themost common lipid-related molecules involved in oxida-tion and lipid deposition include oxidized cholesterols,apolipoproteins (apo), and oxLDL.Oxidized cholesterolsOxidized cholesterols are a category of molecules thathas been extensively studied. While oxidized cholesterolsare involved in AMD, AD and AS, they do not appear tobe significantly involved in GN. 7-ketocholesterol (7kCh)is one of the important oxidized cholesterols involved inAMD. 7kCh deposits has been found at BrM, chorio-capllaris and endothelial cell surfaces [41]. It inducedvascular endothelial growth factor production in RPEcell cultures and has been linked to choroidal neovascu-larization in the wet form of AMD [41]. In AD, 7kChsensitizes the cell membranes to interact with Aβ, animportant peptide in AD pathogenesis, although theinteraction was not strong enough to induce down-stream pathogenic events such as intracellular transferof the peptide [42, 43]. K+ homeostasis disruption, an-other contributor to AD pathogenesis, is also triggeredby 7kCh [44]. Given these functions of 7kCh in AD, itwill be interesting to see if 7kCh sensitizes RPE cellmembrane’s interaction with other lipid-related mole-cules, such as apo, or if it disrupts ion channels in RPEcell membranes. There are hundreds of papers in the lit-erature suggesting 7kCh’s association with AS. Many ex-plore the cellular mechanisms underlying the damageinduced by 7kCh. It was repeatedly shown that 7kCh ef-ficiently induced apoptosis and cytotoxicity in endothe-lial cells [45, 46]. Related to cell damage, 7kCh wascapable of inducing intracellular ROS production inendothelial cells [46]. Since ROS production in RPE cellsis associated with AMD, it is worthwhile to investigate ifoxidized cholesterol molecules induce ROS productionin RPE cells. Further, it has been reported that in vascu-lar smooth muscle cells, 7kCh treatment is able to in-crease cholesterol levels in a dose-dependent manner[47]. Given that cholesterol is the major component ofAS plaques, 7kCh may be an important inducer of ASplaque formation.Cholesterol may also be oxidized on the side-chains.One of these molecules, 24-(S)-hydroxycholesterol(24S–OHC), is involved in both AMD and AD. In AMD,they are capable of causing increased Aβ production,ROS production, inflammation and apoptosis in a RPEcell line [48]. In AD patients, higher plasma levels of24S–OHC were found compared to controls [49]. Inmurine oligodendrocytes, which work closely with brainneurons, both 7kCh and 24S–OHC can trigger K+homeostasis disruption, suggesting a pathogenic role ofthese two molecules in AD [44]. Both 7kCh and a closerelative of 24S–OHC, 25-hydroxycholesterol (25OH),were found to enhance morphological cellular changesafter the cell membrane associates with Aβ [42]. In an-other study, while 7kCh could not elicit more cellular re-sponse than increased cell membrane-Aβ association,25OH was capable of inducing membrane raft-dependent transport of Aβ in Jurkat cells [43]. This sug-gests that hydroxycholesterols might be a more potentinducer of cellular changes. Interestingly, this type of ox-idized cholesterol was also reported to be a remedy topathology. In human neuroblastoma cells, 24S–OHCtreatments protected the cells from 7kCh-induced cyto-toxic cell death [50]. This interesting evidence in ADsuggest that investigations into the role of these side-chain oxygenated cholesterol may help us to understandRPE cellular changes in AMD.CholesterolCholesterol itself is associated with the lipid deposits, al-though the role of non-oxidized cholesterol in diseasedevelopment is unclear. Only a small number of studiesreported a significant increase in AMD risk with highlevels of total cholesterol [51]. Some studies suggest nosignificant association between total cholesterol andAMD, while others show an inverse relationship [51]. Amouse model showed that lipoprotein accumulation andcholesterol esters presence in the BrM caused the devel-opment of structural changes that signifies aging, butnot to the extent where AMD develops [52]. A ratmodel demonstrated that while 7kCh ocular implantscaused massive angiogenesis and inflammation, choles-terol implants caused no angiogenesis and very little in-flammation [53]. In AD, while 7kCh enhanced the cellmembrane’s interaction with Aβ in cell-sized liposomes,cholesterol inhibited this crucial event in AD pathogen-esis [42]. Therefore, non-oxidized cholesterol may nothave an impact on the pathogenesis of these diseases.ApolipoproteinsAs previously described, lipids and proteins are the majorcomponents of drusen [32]. Related to lipid molecules,apolipoproteins (Apo) are also important components ofthe lipid-rich deposits. Lipid metabolism is governed byApo, which are structural proteins that are integral to themetabolism of triglycerides and cholesterol in the body. InAMD, RPE secretes Apo into the BrM, which accumulateswith aging and forms a lipid barrier that retards the trans-portation of oxygen, nutrient and waste products [51].Importantly, this lipid barrier is the cradle for drusen for-mation. In AD studies, immunostaining experimentsrevealed that apolipoprotein E (ApoE) and cholesterol co-localizes with Aβ in SPs of mouse models [54]. OtherXu et al. Lipids in Health and Disease (2018) 17:3 Page 4 of 13immunoreactivity experiments showed the presence ofApoE, low-density lipoprotein (LDL) receptor and LDLreceptor related proteins in SPs [55]. Further, Sun and col-leagues directly suggested that preferential uptake ofoxidized lipoproteins might function as an oxidative stres-sor itself and initiate neuronal cell death to cause AD [56].Apo is also found in atherosclerotic plaques. The“response to retention” hypothesis of atherosclerosis sug-gest that subendothelial lipoprotein retention initiates ASpathology [57]. The same hypothesis has been used todescribe similar steps in AMD pathogenesis [58]. In ASand AMD, shared lipoprotein by-products, such as linole-ate hydroperoxide and 7kCh, are identified in the aorticintima and the BrM [41, 59]. In MPGN II, Apo have beenfound in the microdissection samples of MPGN II with100% probability by mass spectroscopy [38].Furthermore, Apo is an important constituent of LDL,composed of mainly cholesterol and protein along withother lipid-related molecules. Specifically, oxidized LDL(oxLDL) has been found in lipid deposits of both AMDand MPGN. Immunohistochemistry studies revealed thepresence of oxLDL in surgically removed choroidal neo-vascular membranes from eyes of AMD patients [60]. Inmesangial matrix of kidney, accumulation of oxLDL cancause cytotoxicity, increase the cross-linking of glycatedmatrix components and establish conditions that favourmesangial sclerosis [61]. Given the evidence of Apo’sinvolvement in all four diseases, it is possible that Apo isa lipid-related molecule universally involved in manyoxidation and inflammation-related diseases. Investiga-tions into targeted treatment to lower Apo or regulateApo secretion from certain cells, such as RPE cells,may yield effective treatment that works for multiplediseases.Genetic variations in genes regulating lipid metabolism,such as the APOE gene coding for apolipoprotein E,constitute important risk factors for AMD, AD, and AS.The APOE-4 allele was associated with a decreased risk ofAMD, while the APOE-2 allele was associated with anincreased risk of AMD for males in population studies [62,63]. Differences are apparent among the other diseasesstudied here, as in AD it is well established that APOE-4allele is the most prevalent risk factor [64]. Both late-onsetfamilial AD and sporadic AD have increased prevalence ofAPOE-4 alleles compared to controls [55]. Mechanistically,the protein coded by APOE-4 binds to Aβ and prevents Aβfrom being degraded by neprilysin, thus promoting itsaggregation [2]. Furthermore, APOE-4 interacts withcerebral spinal fluid (CSF) amyloid and CSF hyperpho-sphorylated tau protein (ptau) and exerts a synergisticrelationship with complement protein C3 to causepathology and neurodegeneration [65]. Although weunderstand some of the mechanisms in which Apo work,one question still lingers. Why would different types of Apohave such contrasting effects in related diseases such asAMD and AD?In AS, gene variants related to atherosclerosis throughcarotid intimal-medial wall thickness include genesrelated to matrix deposition (MMP3), inflammation(interleukin 6), and lipid metabolism (hepatic lipase,APOE, CETP, and PON1) [Reviewed by [66]]. Thisevidence supports the interaction between at risk lipidmetabolism and inflammatory responses. Other varia-tions in cholesterol-related genes are also important riskfactors for AMD. For example, gene variants of choles-teryl ester transfer protein (CETP), hepatic lipase (LIPC),and ATP-binding cassette transporter A1 (ABCA1),are cholesterol-related genes that are involved inAMD [Reviewed by [23]]. These genes code for pro-tein products involved in cholesterol transport andmetabolism. Given the variety, complexity and re-latedness of lipid metabolism genes, composing amind map of their relationship will aid the identifica-tion of important genes involved in the pathogenesisof lipid-related diseases.CEPCarboxyethylpyrroles (CEP) are phospholipid-modifiedprotein adducts that are closely involved in the patho-genesis of AMD [67]. In the eyes, CEP accumulates inthe RPE and photoreceptor outer segments [67]. InAMD, CEP-modified proteins are present at higherlevels in drusen, retina and blood [67]. CEP-modifiedproteins are also present in the brain, although insteadof AD, they are related to autism [67]. In AS, CEP wasfound in human AS lesions both within and outsidemacrophages [68]. In mice fed with Western diet,immunofluorescence experiments showed CEP accumu-lation in their aortic root [68]. Although we know thatCEP is associated with oxidative stress and inflammatorysignals in macrophages [69], and that both processes areinvolved in AD and GN, CEP are not specifically associ-ated with these two diseases. Therefore, investigating therole of CEP in AD and GN pathology may yield fruitfulresults. There are many other types of modified-proteinsinvolved in AMD, such as aldehyde-modified proteinsand 4-hydroxynonenal-modified proteins [70, 71]. Sincethis review focuses mainly on lipid depositions anddownstream consequences, they are out of the scope ofthis review.BisretinoidsBisretinoids, components of lipofusin, are another cat-egory of lipid-related molecules that plays an importantrole in AMD. Oxidized bisretinoids directly activate thecomplement system, most likely through the alternativepathway [72], as shown by in vitro experiments on hu-man RPE cells [73]. Bisretinoids are degraded whenXu et al. Lipids in Health and Disease (2018) 17:3 Page 5 of 13short-wavelength light hits the retina and this type ofphotodegradation is ongoing in the eye [74]. In the eye,photodegradation of certain bisretinoids, such as A2Eand all-trans-retinal dimer, generates dicarbonyls glyoxal(GO) and methylglyoxal (MG) [75]. In AMD, these by-products modify proteins by advanced glycation endpro-duct (AGE) formation [75]. In AS, proteins are alsomodified by MG and GO by non-enzymatic glycationand oxidation reactions, in addition to AGE formationas in AMD [75]. Just like CEP, bisretinoids are notreported to have significant roles in AD or GN.InflammationInflammation plays an important role in AMD, AD,AS and GN. Under normal circumstances, appropriateactivation of the inflammatory process help the bodyto remove waste materials and apoptotic cells, pro-tecting the individual from disease development. Forexample, the initial purpose of complement activationin AD may be simply to remove Aβ plaques. Withoutcomplement activation, AD mice displayed higher Aβdeposition and more severe neurodegeneration whencompared to mice of the same age [76]. In AS, theclassic complement factor C1q reduces early AS inmouse models [77]. Likewise, macrophages may havea beneficial role in the treatment of AD. In mousemodels, weekly injection of macrophage colony stimu-lating factor (M-CSF), a factor that allows microgliato differentiate into macrophage-like cells, preventedcognitive loss and resulted in smaller and less denseSPs [78].However, excessive and inappropriate inflammationcan cause tissue damage and thus inhibiting excessiveinflammation may control disease progression. One ofthese inhibiting factors is complement factor H (CFH).BrM specimens from AMD patients confirmed thatthe presence of CFH, a major inhibitor of the alterna-tive complement pathway, removes lipoproteins andserves as a protective factor in disease progression[79]. Excessive inflammation in the brain also leads topathogenesis. When macrophages in the brain fail toclear excess Aβ proteins, they become chronically ac-tivated and cause neuronal damage by secreting neu-rotoxins such as free radicals, nitric oxide, cytokinesand N-Methyl-D-aspartic-acid-like molecules [80, 81].Complement activation and macrophage recruitmentare two major inflammatory pathways involved in thepathogenesis of AMD, AD, AS and GN (Fig. 1). Wewill discuss them in more detail in the followingsections.Fig. 1 Lipid-related common pathogenic mechanisms in AMD, AD, AS and GN. Various oxidative sources cause lipid-related molecules toundergo oxidation, which then accumulate in the site of disease progression. Depending on the type of deposit, these accumulations lead todifferent pathologies. Common among the different pathologies, these lipid-rich deposits activate inflammation through complement activationand macrophage recruitment. Many complement proteins and CFH-related polymorphisms are involved in the four diseases discussed in thisreview. Macrophages are recruited and further differentiated due to the presence of various cytokines as well as lipid transport metabolismXu et al. Lipids in Health and Disease (2018) 17:3 Page 6 of 13Complement activationIn AD, complement factor B and associated by productsof the alternative complement system are increased inthe frontal cortex of AD patients [82]. Interestingly inAD, C3 and ApoE have a significant interaction on bothCSF Aβ and CSF ptau [65]. In contrast to AMD, the in-hibitory factor H and factor I were not significantlyincreased in AD. In a mouse model of AS, mRNA andqPCR analysis showed the presence of alternative path-way components in mice under diet-induced AS condi-tions [83]. These include C3, properdin, and factor D.Specifically, C3 was found in aortic lesions. In MPGN,components of the alternative complement pathwaywere identified in almost all dissected glomeruli samplesin a 2009 study [38]. Mass spectroscopy experimentsidentified the presence of complement components,including C3, C5, C8α, C9, Complement Factor HRelated Protein 1, vitronectin and ApoE in laser micro-dissections of MPGN glomeruli with 100% probability[38]. The breakdown products of C3, including C3β andC3β chains, are also identified in the dissections andreported to be the components that were buried away inthe glomeruli [38]. Together, this evidence supports theclose involvement of alternative complement pathway inthe four diseases. Although each disease may involveslightly different molecules, regulation of the alternativecomplement pathway is a common target for futureresearch. The significant molecules involved in relateddiseases will also serve as a library in which we can tar-get specific molecules to study in AMD models.Closely functioning together with the alternative com-plement pathway, genetic variations in CFH also appearto be important in AMD, AS and GN. In human eyeswith AMD, CFH co-localizes and binds with oxidizedlipids in drusen [84]. Specifically, CFH variant 402Y ofthe protective rs1061170 genotype have a higher affinityfor oxidized lipids and more effective inhibition of oxi-dized lipid interaction with RPE and macrophages [84].On the other hand, the CFH risk allele 402H is corre-lated with a lower capacity to inhibit the induction ofthe complement system and so increased risk of AMD[84]. This polymorphism seems to be specific to AMD,as scientists are unable to detect an association ofY402H polymorphism with AD, AS, and insufficient lit-erature is established around Y402H and GN [85, 86].Therefore, studies around this CFH gene variant may beparticularly informative for unique pathology involved inAMD. Inflammatory protein gene variants, such as inter-leukin 6 and the pro-inflammatory protein chymase, areassociated with increased risk factor for AS [66, 87].Although there is a lack of information specificallyaround CFH Y402H polymorphism and GN, the litera-ture suggests an interesting connection between AMD,GN and CFH. After reviewing patient family history andperforming genome linkage scans, it was found that thesuggested MPGN risk locus (chromosome 1q31–32)physically resides near an AMD risk region (chromo-some 1q-31) [5, 6]. This chromosome location is part ofthe region that harbours CFH genes and later has beensuggested to be an AMD susceptibility locus [88]. Sincethere are at least eight common single nucleotide poly-morphisms associated with AMD [88], it will be interest-ing to see if further CFH gene variations are sharedbetween AMD and GN, which might direct futureresearch around CFH genetics.Other types of mutation in CFH and its related pro-teins suggest that CFH-related mutations might beworthwhile targets of research for both AMD and GN.A case study involving both AMD and MGPN showedthe patient expressing an heterozygous amino acid sub-stitution mutation of the CFH protein, namely the mis-sense mutation in exon 9 of CFH (c.1292 G > A) [89]. Inaddition, the patient was homozygote for the CFHY402H allele. After characterizing the subject’s CFHalleles at other positions, researchers concluded that thisprototypical complement genetic profile might include apartial CFH deficiency and serve as major risk factorsfor both AMD and MPGN. Related to CFH function, acase study of poststreptococcal glomerulonephritisshowed that a heterozygous single nucleotide insertionmutation in Complement Factor H–Related Protein 5resulted in a premature stop codon and decreased pro-tein levels in the serum [90]. The researchers speculatethat this variant may be a risk factor for this type of GN.The other major arm of complement, the classicalcomplement pathway, seems to be involved primarily inAMD and AD, while some literature also support itsinvolvement in AS and GN. The classical complementpathway appears to be involved in AMD pathogenesis byqPCR analysis that showed expression of classicalpathway-related transcripts in choroid, RPE and neuralretina [91]. The same study also suggested that cells inthe choroid are the main sources of classical pathwaygene expression [91]. Expression of C1 inhibitor factorin AMD supports this finding [92]. RNA studies showthat while many classical pathway-related complementproteins are expressed at higher levels in AD brains,increase in C1q and C9 expression was particularly dra-matic [93]. The sources of these complement proteinsare found to be likely reactive glial cells and pyramidalneurons by in situ hybridization and immunohistochem-istry experiments [94, 95]. In both AMD and AD,sources of classic complement components lie in thesupporting cells. The current research of AMD focusesmainly on RPE cells. Shifting our attention to choroidalcells and classical complement activation maybe fruitful,especially in the area of wet AMD pathogenesis. Severalprotein markers in AD were reported to activate theXu et al. Lipids in Health and Disease (2018) 17:3 Page 7 of 13classic complement pathway. Using direct in vitroevidence and indirect in situ evidence, Rogers and col-leagues report that the cytotoxic Aβ binds and activatesthe classical complement pathway. They also reportseeing these actions specifically localized to the brainareas where AD pathology occurs [96]. Later, molecularexperiments showed that Aβ is capable of activatingboth the classical and alternative pathways [97]. Interest-ingly, the other important diagnostic protein of AD, tau,is also reported to activate the classical complementpathway [98]. Using both in vitro and in situ evidence,Shen and colleagues report that the pre-clinical presen-tation of both Aβ and tau protein may lead to chronicinflammation in AD [98]. Related to this finding in AD,Aβ is also found in the neuroretina [99]. Possibly, Aβ iscapable of inducing macrophage recruitment and forma-tion of membrane attack complex in the retina [99, 100].Currently, our lab has conducted studies around the as-sociation of Aβ and classical pathway activation in AMD(unpublished data). In rodent models, anti-Aβ drug trialsrepeatedly relieved retinal deficits associated with AMD[101, 102].Although there is a large body of literature supportingcomplement’s involvement in the pathogenesis of AMD,AD, AS and GN, the mechanisms by which the comple-ment system induces damage are complex. Descriptionsof the cascades leading to classic, alternative and leptincomplement pathway activation in each disease are outof the scope for this review. For a review of complementsystem activation and possible relationship betweenAMD and AS, see [103]. A recent review by Heppnerand colleagues nicely summarizes the inflammatory pro-cesses in AD [104]. Complement’s involvement in glom-erular diseases is reviewed by [105].Macrophage recruitmentBesides direct cellular attack using membrane attackcomplex, one of the key functions of the complementpathway is to facilitate the phagocytosis of foreign path-ogens by macrophages. Macrophages play a key role inAMD, AD, AS and GN and its recruitment rely on che-mokines. In AMD, monocyte chemoattractant protein-1(MCP-1), is found in high concentration in RPE cells[106]. MCP-1 acts in concert with other chemokinesand cytokines to recruit macrophages and other immunecells to accumulate in areas surrounding drusendeposits. It is unclear if the arrival of macrophages isprotective against AMD or facilitative of drusen forma-tion. However, there is evidence supporting a correlationbetween the extent of macrophage phenotypic changesand the clinical stages of AMD [107, 108]. Since macro-phages are closely associated with AMD disease progres-sion, drawing understanding of macrophage recruitmentand regulation from other related diseases might help tofurther understand their role in the development ofAMD.Microglia and peripheral macrophages are both associ-ated with the progression of AD. Chronic activation ofmicroglia is thought to induce neuron injury. Isolatedproteins of neuritic and SP stimulate macrophages andmicroglia to secrete neurotoxins through a variety of cel-lular pathways, thus damaging neurons [80, 81]. Similarto the idea of stimulating complement activation withtoxic proteins, stimulating macrophage recruitment in invivo AMD models might yield understanding of macro-phage chemoattractant profile in AMD. Interestingly,non-resident macrophages that infiltrate into the brainare suggested to have more phagocytic capacity thanmicroglia, the resident macrophages in the brain [109].Supporting the idea that peripheral macrophage mustmigrate into the disease site in order to exert its actions,the proinflammatory cytokine macrophage migration in-hibitory factor (MIF) was found to be up-regulated inthe cerebrospinal fluid of AD patients, suggesting thatdecreased capability of macrophage migration may con-tribute to AD [110]. Differentiation of microglia intomacrophage-like cells relies on macrophage colonystimulating factor (M-CSF). Expression of this factor andits receptor is increased in a mouse model of AD and itappears to augment the effect of Aβ on microglia activa-tion in in vitro experiments [111]. Unlike in AD, there islimited knowledge about the source of macrophages andits relation to AMD disease progression. Further studymay be conducted to see whether choroidal macrophage,peripheral monocyte or retinal microglia have the mostphagocytic capacity. Macrophage recruitment has beenassociated with glomerular injury in many diseases in-cluding GN. In immune mediated GN, macrophages be-come activated in the inflamed glomerulus and releasespro-inflammatory cytokines as well as ROS to causeglomerular basement membrane damage and fibrin de-position. Similar to AD, MIF was significantly up-regulated in a mouse model of autoimmune GN [112].When these mice were genetically edited to have defi-cient MIF, renal macrophage recruitment and glomeru-lar injury were significantly lowered [112]. Humanstudies also show evidence supporting the pathologicalrole of MIF. In biopsies of GN patients, MIF expressionwas markedly increased in proliferative GN conditions[113]. This correlates to T-cell and macrophage infiltra-tion in histological lesions. Combining with the evidencefrom AD studies, macrophage recruitment from the per-iphery is likely a compensatory mechanism to clear outtoxic molecules. However, excessive macrophage activa-tion and differentiation into M1/M2 subtype in AMD orfoam cells in AS is clearly pathogenic.Lipid accumulation inside macrophage is related to itsdifferentiation. It has been suggested that defective ATP-Xu et al. Lipids in Health and Disease (2018) 17:3 Page 8 of 13binding cassette transporters in older macrophagesresult in accumulation of intracellular cholesterol, whichthen induce a phenotypic change from M1 pro-inflammatory macrophage to M2 pro-angiogenic macro-phage [114]. After the change in macrophage phenotype,these cells produce different cytokines, express differentreceptors and perform different effector functions whichmay promote the transition from dry AMD to wet AMD[115]. In AS, lipoproteins cross into the arterial walls,bind proteoglycans and become oxidized to induceinflammation, macrophage recruitment and neovascular-ization. Arterial wall macrophages retain cholesterol-containing LDL through receptor mediated uptake orfluid-phase pinocytosis, which are reported to be veryimportant events in atherosclerosis pathogenesis [23].The two phenotypes of macrophages, M1 and M2, arefound in atherosclerotic plaques and are distributedaccording to their functions [116]. Although there aremany similarities between the lipid deposits in AMDand AS, it should be noted that the sources of the accu-mulated lipids differ. While the lipids in atherosclerosiscome mostly from the plasma, the lipids in AMD mayhave a plasmatic or intraocular source [117, 118]. Giventhe contradictory roles of different types of macro-phages, it is worthwhile to investigate the mechanismand regulation of macrophage recruitment and its fur-ther differentiation, in order to simultaneously harvesttheir benefits and prevent disease progression.Treatments for AMD, AD, AS and GNCurrently, there is ongoing research around the treatmentfor each disease discussed in this review. This review pro-vides an overview of available treatments and potentialnew research directions pertaining to these diseases.Current AMD treatments mainly focus on delayingdisease progression. Although there are no effectivetreatments for early nonexudative AMD, nutritional sup-plements have been suggested to help protect againstAMD progression. In the AREDS studies, supplementa-tion with a combination of high dose vitamin C, vitaminE, beta-carotene, and zinc was shown to significantlydecrease the odds for advanced AMD [119]. Follow upstudies suggested that addition of lutein/zeaxanthin tothe AREDS combination formula might be more appro-priate than beta-carotene [120]. For the exudative formof AMD, approved treatments may include intravitrealanti-vascular endothelial growth factor injections orphotodynamic therapy [121]. AD treatments mostly ad-dress symptoms without slowing the progression of dis-ease or curative effects. Psychotropic medications treatthe symptoms of AD by addressing specific secondarymanifestations such as depression, agitation and halluci-nations [122]. Newer AD treatment trials include mono-clonal anti-Aβ antibodies, which did not showsignificant efficacy [123]. For a more in depth discussionabout this treatment, please refer to [123]. Commontreatments for AS include statins to lower LDL andcholesterol, fibrates to reduce triglycerides (TG), niacinto reduce TG and LDL. Treatment goals include lower-ing LDL cholesterol, non-HDL cholesterol, and ApoB,some of which cross over with the lipid molecules dis-cussed in this review [124]. Recommended treatment forMPGN II involves corticosteroids to stabilize kidneyfunction, plus both cyclophosphamide and mycopheno-late mofetil to suppress the immune system [125]. Giventhis knowledge about the currently available treatments,there are other potential areas where investigation islikely worthwhile.Since there are no current treatments for early non-exudative AMD and AD, it may be worthwhile to inves-tigate the effect of adding ROS suppressing agents to theAREDS combination formula while simultaneously treat-ing risk factors in these two disease models. ROS gener-ation appears to be a common factor in various theoriesof AD pathogenesis and ROS suppression may be apromising method to better treat AD [126]. However,clinical trials of antioxidants have not yield fruitfulresults in treating AD [127]. Although antioxidants, suchas the natural spice Curcumin, may not individually pro-duce clinical efficacy, its combination with other therap-ies and its administration earlier in the disease historymay warrant more research [128]. In AS, lipid loweringagents are established but not without their caveats.Although endogenous Coenzyme Q10 is the most activeantioxidant in human, statin treatment have been foundto decrease this natural defense mechanism [129, 130].Investigations are warranted to solve this adverse inter-action or more effort may be indicated to recommenddietary avoidance of oxidized cholesterols in commer-cially fried foods and polyunsaturated fatty acids. Drugsthat resemble our endogenous antioxidant CoenzymeQ10 might be able to address the oxidized versions ofcholesterol such as 7kCh or 24S–OHC discussed in thisreview. For apolipoproteins, drugs that lower ApoBlevels are effective treatments for AS, but no treatmentexists for lowering the subtypes of ApoE that are associ-ated with AMD and AD. Since anti-Aβ antibodies dem-onstrated limited efficacy, one potential direction is toturn our research attention to pharmacological agentsthat target ApoE. By addressing Apo levels in the body,it may be possible to control the source of inappropriateinflammation and preserve appropriate inflammation fornormal body responses.ConclusionAMD, AD, AS and GN are related in many aspects. Ageneral scheme of pathogenesis may be shared betweenthe four diseases. Under macroscopic oxidativeXu et al. Lipids in Health and Disease (2018) 17:3 Page 9 of 13environments and microscopic ROS stress, lipids becomeoxidized and begin to deposit in the sites of disease devel-opment. These lesions cause an increased inflammatoryresponse by activating the complement system as well asrecruiting macrophages. As excessive inflammatory dam-age builds up, pathologic events occur in the eye, brain,blood vessels and kidneys. Shared genetic variations be-tween the diseases further strengthen their connectionand support common mechanisms of pathogenesis. By fo-cusing on the similarities in lipid deposits and their conse-quences, this review reported common pathologicalmechanisms shared between AMD, AD, AS and GN,established a framework of ideas to aid understanding ofAMD pathogenesis and provided novel strategies tosearch for more effective therapies.Abbreviations24S–OHC: 24(S)-Hydroxycholesterol; 25OH: 25-hydroxycholesterol; 7kCh: 7-ketocholesterol; AD: Alzheimer’s disease; AGE: Advanced glycationendproduct; AMD: Age-related macular degeneration; ApoE: ApolipoproteinE; AS: Atherosclerosis; Aβ: Amyloid-β; BrM: Bruch’s membrane;CEP: Carboxyethylpyrroles; CETP: Cholesteryl ester transfer protein;CFH: Complement factor H; CSF: Cerebral spinal fluid; GBM: Glomerularbasement membrane; GN: Glomerulonephritis; GO: Dicarbonyls glyoxal;LIPC: Hepatic lipase; MCP-1: Monocyte chemoattractant protein-1; M-CSF: Macrophage colony stimulating factor; MG: Methylglyoxal;MIF: Macrophage migration inhibitory factor; MPGN II: Membranoproliferativeglomerulonephritis type II; MPGN: Membranoproliferative glomerulonephritis;oxLDL: Oxidized LDL; Ptau: Hyperphosphorylated tau protein;qPCR: Quantitative polymerase chain reaction; ROS: Reactive oxygen species;RPE: Retinal pigment epithelium; SP: Senile plaquesAcknowledgementsNot applicable.FundingThis literature review article is made possible by UBC Faculty of Medicine,Department of Ophthalmology and Visual Sciences, CIHR and VancouverCoastal Health. The funding body had no role in the design of the study andcollection, analysis, and interpretation of data and in writing the manuscript.Availability of data and materialsNot applicableAuthors’ contributionsAX contributed to the study conception and design of the work, drafting ofthe manuscript, figure preparation and she is accountable for all aspects ofthe work. SC contributed to conception and design of the work, revising andcritically editing for important intellectual content and she is accountable forall aspects of the work. SR contributed to the editing, initiation, conception,and design of the work. JM contributed to conception and design of thework. She also contributed by revising and critically editing the manuscriptfor important intellectual content. She is accountable for all aspects of thework and responsible for final approval of the version to be published. Allauthors read and approved the final manuscript.Ethics approval and consent to participateNot applicableConsent for publicationNot applicableCompeting interestsThe authors declare that they have no competing interests.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Received: 18 September 2017 Accepted: 17 December 2017References1. Resnikoff S, Pascolini D, Etya’ale D, Kocur I, Pararajasegaram R, Pokharel GP,et al. Global data on visual impairment in the year 2002. Bull. World HealthOrgan. 2004;82:844–851. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15640920%5Cn. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC2623053.2. Ohno-Matsui K. Parallel findings in age-related macular degeneration andAlzheimer’s disease. Prog. Retin. Eye res. 2011;30:217–238. Available from:https://doi.org/10.1016/j.preteyeres.2011.02.0043. Klein R, Klein BEK, Unton KLP, Demets DL. 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