Table 1.

Summary of Current Age-Related Macular Degeneration Mouse Models

	Mouse model	Abbreviation	Comments	References
Mouse models of “early” and “intermediate” AMD	Acid sphingomyelinase (ASMase) knockout (KO) mouse	ASMase− /−	Deficiency of ASMase leads to age-dependent visual loss, photoreceptor degeneration, and increased RPE autofluorescence that correlates with decreased retinal sphingomyelin levels and increased eyecup autophagy.	131
	Human apolipoprotein B100 (APOB100) mouse fed a high-fat (HF) diet	APOB100∼HF	C57BL/6J mice that contain the full-length human APOB gene were fed a HF diet and aged to 12 months but no apparent phenotypic differences were observed between APOB100 mice fed a normal mouse chow and HF diet.	77
	Apob100 mouse fed a low-fat (LF) diet	Apob100∼LF	Mice with Apob mutation that prevents the formation of the alternatively spliced Apob48 variant was used to evaluate LXR agonists.	100,101
	Apolipoprotein E (Apoe) KO mouse fed a high cholesterol (HC) diet	Apoe−/−∼HC	4–5-week-old Apoe−/− mice were fed a HC diet for 25 weeks and had worsened retinal pathologies relative to controls.	78,79
	Human apolipoprotein E isoform 4 (APOE4) mouse fed a high-fat, cholesterol-enriched (HFC) diet	APOE4∼HFC	Aged APOE4∼HFC develop more severe AMD-like pathology than aged APOE2 and APOE3 mice fed a HFC diet.	80,81
	Aryl hydrocarbon receptor (Ahr) KO mouse	Ahr− /−	Chronic mouse model based on AHR activity and protein concentration decreases with age in human RPE cells.102	102
	C57BL/6J mouse exposed to cigarette smoke (CS)	C57BL/6J∼CS	2-month-old C57BL/6J mice were exposed to cigarette smoke for 5 h a day and 5 days a week for 6 months that resulted in ultrastructural changes to BrM and RPE apoptosis.	132
	C57BL/6J mouse fed a HF diet	C57BL/6J∼HF	6-week-old C57BL/6 mice fed a HF diet for 30 weeks developed decreased ERGs, increased fundus abnormalities and thickened BrM.	82
	C57BL/6J mouse fed a high glycemic (HG) diet	C57BL/6J∼HG	16-month-old C57BL/6J mice were fed a HG diet until 23.5 months of age and developed more AMD-like pathologies that correlated with changes in the microbiome.103	103,104
	Complement membrane cofactor protein (Cd46) KO mouse	Cd46−/−	Loss of CD46, a membrane regulator of complement activation, leads to age-dependent mice increases in RPE autofluorescence and BrM thickness as well as decreases in choroidal thickness in mice.	124
	C57BL/6J mouse immunized with carboxyethylpyrrole (CEP)-adducted BSA	CEP immunized C57BL/6J	Chronic mouse model with increased inflammasome activation133 and increased proinflammatory macrophage infiltration.134	105
	Collagen-induced arthritis (CIA) in C57BL/6J mouse	CIA Induced C57BL/6J	Mouse model of systemic inflammation that had decreased laser-induced CNV lesion size but worsened RPE pathologies after sodium iodate treatment.	135
	Ceruloplasmin (cp) and hephaestin (Heph) double KO mouse	Cp−/− Heph− /−	Chronic mouse model in which pathologies result from increased oxidative stress from retinal iron overload as supported by the protection against pathologies with the iron chelator deferiprone.136	106,107
	Complement factor h (Cfh) KO mouse	Cfh− /−	Absence of CFH leads to excess complement activation resulting in no reservoir of plasma complement proteins and subtle retinal damage in aged Cfh−/− mice.	108,109,137
	Heterozygous Cfh KO mouse fed a HFC diet	Cfh+/−∼HFC	Aged Cfh+/−∼HFC provides the first multifactorial AMD mouse model suited to test the role of complement components on AMD-like pathology development such as C5a.138	21
	Human complement factor H (CFH) Y402 and H402 mouse	CFH,Cfh−/−	Transgenic mice expressing the full-length human CFH gene encoding either the Tyrosine (Y) or Histidine (H) at amino acid 402 were crossed to Cfh−/− mice to generate mice that produce only human CFH Y402 or H402 protein, respectively, which functions with mouse complement proteins.	109
	Human complement factor H (CFH) Y402 and H402 mouse aged and fed a HFC diet	CFH∼HFC	Phenotypic differences in ocular phenotypes, circulating lipoproteins and ocular lipoproteins were noted between mice expressing equal concentrations of either the CFH Y402 or H402 variant. Only CFH-H/H develop AMD-like phenotype	20
	Chimeric, transgenic Cfh mouse	Chimeric Cfh	Mouse Cfh was genetically modified to include short consensus repeat domains 6 through 8 of human CFH and included either the Y402 or H402 amino acid but no difference in phenotype was observed between mice expressing these variants.	110
	Mutant Cfh and Complement factor P (fP) KO mouse	fHm/m, fP−/−	Mice with a premature stop codon in the end of exon 19 of the mouse Cfh gene that results in complement activation139 crossed to fP KO mice generated increased sub-RPE basal deposits at an early age.	140
	C-X-C chemokine receptor type 5 (Cxcr5) KO mouse	Cxcr5−/−	Cxcr5−/− mice have increased sub-RPE deposits containing amyloid beta and C3a111 that may result from disrupted PI3K/AKT signaling and FOXO1 upregulation.112	113
	Cxcr5 and nuclear factor-like 2 (Nrf2) double KO mouse	Cxcr5−/−,Nrf2−/−	Combined deficiency of Cxcr5 and Nrf2 worsens AMD-like pathologies observed in both Cxcr5 and Nrf2 KO mice.	141
	Lysosome-associated membrane protein-2 (Lamp2) KO mouse	Lamp2−/−	Absence of LAMP2 in mice leads to the acceleration of sub-RPE basal laminar deposits that contain extracellular matrix proteins, lipoproteins, and cholesterol.	114
	Microtubule-associated protein 1 light chain 3 B (LC3B) KO mouse	LC3B−/−	LC3B KO mice have increased phagosomes, decreased fatty acid oxidation, RPE lipid accumulation, and subretinal immune cell infiltration.	142
	Nrf2 KO mouse fed a HF diet	Nrf2−/−∼HF	12-month-old Nrf−/− mice fed a HF diet for 16 weeks developed a more robust AMD-like phenotype that correlated with interleukin 17-producing γΔ T cells.	83
	Heterozygous peroxisome proliferator-activated receptor-γ coactivator 1α (Pgc1α) KO Mouse Fed a HF Diet	Pgc1α+/−∼HF	Combined Pgc1α heterozygosity and consumption of a HF diet leads to loss of choroidal fenestrations and increased expression of drusen-associated genes.	84
	Pgc1α and Nrf2 double KO mouse	Pgc1α −/−,Nrf2−/−	Combined deficiency of Pgc1α and Nrf2 causes RPE abnormalities and subRPE basal deposits that correlate with damaged mitochondria and increased ER stress.	143
	Peroxisome proliferator-activated receptor-β/δ (Pparβ/δ) KO mouse	Pparβ/δ−/−	Pparβ/δ deficiency leads to increased lipid accumulation and thickened BrM but attenuates laser-induced CNV lesion size.	123
	RPE-specific ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) mouse	RPE ΔAbca1;Abcg1	Absence of ABCA1 and ABCG1 in the RPE leads to increased lipids within the RPE, causing RPE dysmorphogenesis, neuroinflammation, and photoreceptor degeneration.	66
	RPE-specific KO of RB1-inducible coiled-coil 1 (Rb1cc1) mouse	Rb1cc1-CKO	Loss of RB1CC1 in mouse RPE leads to autophagy defects and pathologies, including RPE degeneration, subretinal immune cell infiltration, subRPE deposition of inflammatory and oxidatively damaged proteins, subretinal drusenoid deposits, and CNV that precedes neural retinal abnormalities.	144
	Rod-specific tuberous sclerosis complex 1 (Tsc1) KO mouse	rodTsc1−/−	Mice with rod-specific Tsc1 ablation that leads to constitutive activation of mTORC1 and pathologies resembling those observed in early, late dry, and wet AMD.	122
	Superoxide dismutase 1 (Sod1) KO mouse	Sod1− /−	Chronic mouse model with a susceptibility to oxidative stress damage as shown by increased retinal damage after an intravitreal injection of paraquat.145	115,116
	Superoxide dismutase 2 (Sod2) knockdown mouse	Sod2−/−	Chronic mouse model where Sod2 has been knocked down using a viral-delivered ribozyme and Cre-LoxP recombination that has been used to test the efficacy of RPE65-programmed bone marrow-derived cells in vivo.146	117,118
Mouse models of neovascular AMD	Htra serine peptidase 1 (HTRA1) overexpressing mouse	HTRA1	HTRA1 overexpression was achieved by RPE65 promoter-driven mouse Htra1,129 CMV-BEST1 hybrid promoter-driven human HTRA1128 and CAG-driven mouse Htra1119 expression in wild-type mice and resulted in pathologies after 1 year of age	119,128,129
	Htra1 overexpressing mouse exposed to cigarette smoke (CS)	HTRA1∼CS	12-month-old HTRA1 overexpressing mice were exposed to cigarette smoke for 30 min per day, 5 days per week for 12 weeks, and resulted in increased CNV and sub-RPE basal deposits.	119
	Laser-induced CNV		Commonly used acute model that has been interrogated in multiple transgenic mice (i.e., Cfh−/−,137 Ahr−/−147, and Cx3cr1−/−148 and used for testing novel therapies for wet AMD.	127,149
	Polyethylene glycol (PEG)-induced CNV		Subretinal injection of PEG, a complement activator, leads to CNV in mice 5 days postinjection and is dependent on complement activation.	150
	Very-low-density lipoprotein receptor (Vldlr) KO mouse	Vldlr −/−	Mouse used to model retinal angiomatous proliferation.	151
Mouse models of geographic atrophy	Dicer knockdown mouse	Dicer −/−	Acute mouse model where Dicer has been knocked down by Cre-LoxP recombination and results in increased Alu mRNA and frank RPE cell death mediated by inflammasome activation.152	120,153
	Inducible Cre recombinase driven by the monocarboxylate transporter 3 promoter and Diphtheria toxin A (DTA) with LoxP-flanked stop codon double transgenic mouse	RPE(CreER)/DTA	RPE(CreER)/DTA mice have 60%–80% RPE cell death that results in ERG and retinal pathology and serves as a valuable model for stem cell-derived RPE transplantation studies.	154
	Sodium iodate treatment		Acute insult causing RPE damage resulting in RPE atrophy and death, retinal degeneration, and immune cell recruitment by 3 days postinjection.	125,126,155
	Laser-induced RPE atrophy		Acute mouse model with focal atrophic photoreceptors, abnormal RPE and BrM, visual loss, and neuroinflammation without signs of neovascularization.	156
	Transmembrane protein 135 (Tmem135) transgenic (TG) mouse	Tmem135 TG	Overexpression of Tmem135 leads to fragmented mitochondria in RPE cells as well as progressive RPE degeneration and dysmorphogenesis without affecting visual function until 1 year of age in mice.	121
Acute models of AMD	Blue light exposure		Acute insult that results in damage to the neural retina that has been used to differentiate microglia and bone marrow-derived macrophages in the retina.157	158–160
	Intravitreal injection of paraquat		Acute insult that results in increased oxidative stress damage and subsequent damage to the neural retina that is used for antioxidant therapy studies.	161
	Oral hydroquinone		16-month-old C57BL/6J female mice were given oral hydroquinone in their drinking water that resulted in the development of sub-RPE basal deposits.	162
	White light exposure		BALB/c albino mice treated with white light for 24 h leads to photoreceptor apoptosis and visual loss163 as well as immune cell infiltration that is worsened after CEP immunization.134	163
Mouse models of inherited macular degeneration	ATP-binding cassette, sub-family A (ABC1), member 4 (Abca4) KO mouse	Abca4− /−	Mouse model of recessive Stargardt's disease that is often used in studies on complement activation,164 lipofuscin, and novel drug development for AMD.165	166,167
	C1q and tumor necrosis factor related protein 5 (C1QTNF5) serine to arginine at amino acid 163 (S163R) knockin mouse	C1QTNF5S163R	Mouse model of late-onset retinal degeneration generated by an introduction of the S163R mutation into the mouse C1QTNF5 gene168 as well as viral delivery of human C1QTNF5S163R to the RPE of C57BL/6J mice.169	168,169
	EGF-containing fibulin-like extracellular matrix protein 1 (Efemp1) arginine to tryptophan at amino acid 345 (R345W) knockin mouse	Efemp1R345W	Mouse model of Malattia Leventinese/Doyne's Honeycomb Dystrophy revealed a vital role of complement in sub-RPE deposit formation170 and replicated using cell culture.171	172,173
	Elongation of very-long-chain fatty acids protein 4 (Elovl4) five base pair deletion knockin mouse	Elovl4mut/−	Mouse model of dominant Stargardt's disease characterized by defects in very-long-chain polyunsaturated fatty acids in the retina.174	175,176
	Metalloproteinase inhibitor 3 (Timp3) serine to cysteine at amino acid 156 (S156C) knockin mouse	Timp3S156C	A mouse model of Sorsby's dystrophy used in angiogenesis studies.177	178

AMD, age-related macular degeneration; BrM, Bruch's membrane; CNV, choroidal neovascularization; ERG, electroretinography; LXR, liver X receptor; mTOR, mammalian target of rapamycin; RPE, retinal pigmented epithelium.