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ApoE- and Cfh-deficient mice exhibit structural and molecular features of human early-intermediate retinal degeneration
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Sergio Recalde1, 2, Maite Moreno Orduña1, Jaione Bezunartea1, Idoia Belza1, Ainara Chas1, Laura Fernández-Sánchez3, 4, Nicolás Cuenca Navarro3, 4, Alfredo García-Layana1, 2, Patricia Fernández-Robredo1, 2, María Hernández1, 2
Animal Models and Experimental Medicine | 2026, 9(7) : 1420 - 1435
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Animal Models and Experimental Medicine | 2026, 9(7): 1420-1435
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ApoE- and Cfh-deficient mice exhibit structural and molecular features of human early-intermediate retinal degeneration
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Sergio Recalde1, 2, Maite Moreno Orduña1, Jaione Bezunartea1, Idoia Belza1, Ainara Chas1, Laura Fernández-Sánchez3, 4, Nicolás Cuenca Navarro3, 4, Alfredo García-Layana1, 2, Patricia Fernández-Robredo1, 2, María Hernández1, 2
Affiliations
  • 1Retinal Pathologies and New Therapies Group, Experimental Ophthalmology Laboratory, Department of Ophthalmology, Clínica Universidad de Navarra, Pamplona, Spain
  • 2Navarra Institute for Health Research, IdiSNA, Pamplona, Spain
  • 3Department of Optics, Pharmacology and Anatomy, University of Alicante, Alicante, Spain
  • 4Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain
Published: 2026-07-28 doi: 10.1002/ame2.70243
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Background:

Age-related macular degeneration (AMD) is a multifactorial retinal disease in which alterations in lipid metabolism and dysregulation of the complement system play a central role. The aim of this study was to characterize a novel double-knockout (DK) mouse model deficient in apolipoprotein E and complement factor H (ApoE−/−Cfh−/−) as an experimental model of early and intermediate AMD.

Methods:

ApoE−/−Cfh−/− mice and wild-type controls underwent comprehensive morphological, ultrastructural, biochemical, and molecular analyses. Retinal and retinal pigment epithelium (RPE) integrity, Bruch's membrane (BM) morphology, lipid accumulation, complement activation, angiogenic signaling, and synaptic organization were evaluated using histology, electron microscopy, immunohistochemistry, biochemical assays, and gene expression analyses.

Results:

DK mice exhibited significant RPE thinning, disruption of tight junctions, vacuolization, and BM thickening (p < 0.05). Lipid accumulation and plasma lipid levels significantly increased compared with controls (p < 0.01). Complement activation was significantly enhanced, as evidenced by increased C5b-9 deposition (p < 0.01). In addition, DK mice exhibited increased vascular endothelial growth factor expression (p < 0.05), altered matrix metalloproteinase activity (p < 0.05), and significant synaptic disorganization between photoreceptors and second-order neurons (p < 0.05).

Conclusions:

The ApoE−/−Cfh−/− mouse reproduces key molecular and structural features of early and intermediate retinal degeneration with statistically significant alterations. Although it does not progress to advanced disease stages, it represents a valuable model to investigate several factors of AMD pathogenesis and evaluate therapeutic strategies targeting early disease mechanisms.

aged macular degeneration  /  animal model  /  apolipoprotein E  /  Bruch's membrane  /  complement factor H  /  inflammation  /  lipid metabolism  /  retinal pigment epithelium
Sergio Recalde, Maite Moreno Orduña, Jaione Bezunartea, Idoia Belza, Ainara Chas, Laura Fernández-Sánchez, Nicolás Cuenca Navarro, Alfredo García-Layana, Patricia Fernández-Robredo, María Hernández. ApoE- and Cfh-deficient mice exhibit structural and molecular features of human early-intermediate retinal degeneration[J]. Animal Models and Experimental Medicine, 2026 , 9 (7) : 1420 -1435 . DOI: 10.1002/ame2.70243
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Funding
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  • Inflammatory Disease Network(RD21/0002/0010)
  • Red Nacional de Investigación en Complemento(SAF2016-81876-REDT)
Appendix
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Year 2026 volume 9 Issue 7
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Article Info
doi: 10.1002/ame2.70243
  • Receive Date：2026-02-06
  • Online Date：2026-08-06
  • Published：2026-07-28
Article Data
Affiliations
History
  • Received：2026-02-06
  • Revised：2026-04-30
  • Accepted：2026-05-21
Funding
Inflammatory Disease Network(RD21/0002/0010)
Red Nacional de Investigación en Complemento(SAF2016-81876-REDT)
Affiliations
    1Retinal Pathologies and New Therapies Group, Experimental Ophthalmology Laboratory, Department of Ophthalmology, Clínica Universidad de Navarra, Pamplona, Spain
    2Navarra Institute for Health Research, IdiSNA, Pamplona, Spain
    3Department of Optics, Pharmacology and Anatomy, University of Alicante, Alicante, Spain
    4Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain

Corresponding:

María Hernández, Retinal Pathologies and New Therapies Group, Experimental Ophthalmology Laboratory, Department of Ophthalmology, Clínica Universidad de Navarra, Pamplona, Spain. Email:
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小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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