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Selective retinal neuron loss and impaired neurovascular support underlie myopic retinopathy in RPE-specific Lrp2-deficient mice
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DOI：10.3389/fncel.2026.1856140.png)
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Abstract
En 中文
Pathologic myopia is a major cause of irreversible visual impairment worldwide and is characterized by excessive axial elongation accompanied by progressive retinal degeneration. Whether vision loss results primarily from passive retinal stretching or selective neurodegeneration remains unclear; hindering the development of effective neuroprotective and regenerative therapies. Here; we investigated retinal neuronal; vascular; and glial alterations in retinal pigment epithelium (RPE)-specific Lrp2 knockout (Best1-Cre/Lrp2fl/fl conditional knockout; CKO) model of pathologic myopia. The CKO mice were examined longitudinally using multimodal ocular imaging; electroretinography; optokinetic testing; fluorescein angiography; and quantitative immunohistochemistry analysis. CKO phenotype+ mice developed early-onset; progressive axial elongation and high myopia; accompanied by fundus features closely resembling human pathologic myopia; including peripapillary and patchy chorioretinal atrophy. Retinal function was markedly impaired; with significant reductions in scotopic a-; b-; and c-wave amplitudes. Although axial elongation resulted in a 1.98-fold increase in retinal surface area and a 55.95% reduction in retinal thickness; quantitative correction for retinal expansion revealed selective neuronal loss rather than uniform retinal degeneration. Total numbers of rods; cones; horizontal cells; and GABAergic amacrine cells were reduced by 22; 40; 30; and 57%; respectively; together with a 66% loss of photoreceptor synaptic ribbons. In contrast; retinal ganglion cells and bipolar cells exhibited reduced density but preserved absolute cell numbers. These neuronal changes were accompanied by retinal and choroidal microvascular degeneration; Müller gliosis; microglial activation and subretinal accumulation; and RPE dysmorphology. Our findings demonstrate that axial elongation induces neuron subtype–specific degeneration rather than generalized retinal thinning. Our study identifies photoreceptors; horizontal cells; and inhibitory amacrine cells as particularly vulnerable populations and implicates impaired RPE support; neurovascular dysfunction; and chronic glial activation as key mechanisms driving myopic retinopathy. This study provides a mechanistic framework for developing targeted neuroprotective and regeneration-based therapies for pathologic myopia.
Keywords:
microglia
neurodegeneration
axial elongation
pathologic myopia
microvascular degeneraton
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