Biology subjects

Apte, R. S.

Publications and source records attributed to Apte, R. S..

5 recordsLinked to original sources

bioRxiv2026

Differential Survival of Retinal Ganglion Cell Types Following Branch Retinal Vein Occlusion

Background. Branch retinal vein occlusion (BRVO) is a common cause of retinal ischemia, rapidly inducing neuronal death and often producing irreversible vison loss. Interventions such as thrombolysis restore perfusion but cannot recover neurons already lost, and most patients retain permanent visual deficits. Identifying which neuronal populations die, and how rapidly, may therefore reveal timing windows and targets for neuroprotective treatment. Aims. To determine the timing of pathology, we evaluated vascular changes and neuronal degeneration in a photocoagulation-induced mouse model of BRVO. To determine differences in retinal ganglion cells (RGC) type susceptibility, we tracked the survival of RGC subpopulations using immunofluorescence markers. Methods. BRVO was induced by retro-orbital injection of Rose Bengal and FITC dextran followed by targeted photocoagulation of a branch vein. Obstruction was confirmed by fluorescein angiography and vascular damage was viewed by optical coherence tomography angiography. Cell survival was quantified by immunostaining at 3, 7, and 14 days using RNA Binding Protein with Multiple Splicing (RBPMS, pan RGC). RGC subtype markers for intrinsically photosensitive RGCs (TBR2), RGCs (SPP1), ON OFF direction-selective RGCs (CART), and F RGCs (FOXP2) were used to examine differences in survival across RGC types. Results. Occlusion selectively disrupted the superficial and intermediate capillary plexus, sparing the deep plexuses. All examined neuronal populations were significantly depleted, but with markedly different magnitude and timing. RGCs and F RGCs were the most vulnerable subtypes, both approaching complete loss by one week, whereas intrinsically photosensitive RGCs were the most resistant. Conclusion. RGCs, typically resilient in glaucoma, trauma, and excitotoxicity, were markedly vulnerable in BRVO, indicating that RGC subtype susceptibility is insult-specific.

neuroscience↗

bioRxiv2026

Aberrant retinal structure and vasculature in mouse models of dominant retinopathies caused by CRX homeodomain mutations

CRX is a transcription factor essential for photoreceptor differentiation and functional development. Two missense mutations in CRX homeodomain, CRXE80A and CRXK88N, are linked to early-onset dominant retinopathies. Molecular studies have revealed distinct profiles of perturbed gene expression in differentiating photoreceptors of knock-in mouse models, resulting from altered DNA binding activities of mutant CRX proteins. This study characterizes concurrent retinal and vascular alterations in knock-in mouse models. Fated cones are present in heterozygous and homozygous CrxE80A and CrxK88N mutants at birth, but subsequent cone differentiation is rapidly compromised. Expression of rod marker rhodopsin (RHO) is absent in CrxK88N/Nretinae but present in other mutants through adulthood. Notably, as compared to wildtype controls, RHO expression is prematurely activated in neonatal CrxE80A mutants. Among tested mutants, only CrxE80A/+retinae elaborate rod outer segments but still lose visual function by young adulthood. The presence of irregular retinal rosettes is a striking pathological phenotype in all mutants. Retinal rosettes displace the localization of inner neurons without affecting their cell numbers during retinal development. Retinal vessels develop close contact with rosette structures. In summary, disrupted photoreceptor differentiation leads to the loss of visual function and formation of retinal rosettes. The presence of retinal rosettes secondarily impairs the localization of inner neurons and vasculature. A deeper understanding of these cellular underpinnings will inform pathogenesis of CRX homeodomain mutations.

neuroscience↗

bioRxiv2026

Macrophage immunosenescence prolongs intraocular inflammation in aged mice via impaired induction of regulatory T cells

Immune-mediated intraocular inflammation, called uveitis, is a leading cause of global blindness, with the highest burden of visual impairment falling on older individuals. Immunosenescence, the functional changes in immune cells with aging, impacts the age-associated immune response, but how immunosenescence and the molecular regulators of the age-associated immune response affect the clinical course of uveitis remains unclear. In the murine model of experimental autoimmune uveitis (EAU), aged mice demonstrated a delayed onset and peak of intraocular inflammation compared to young mice. In contrast to the canonical monophasic inflammation that rapidly resolves in young mice, aged mice developed persistent, chronic inflammation. Transcriptomic and flow-cytometric analyses of immune cells and the receptor-ligand interactome revealed a dominant macrophage-CD4+ T cell signature. This signaling pathway was functionally altered on both ends: macrophages from aged mice had an impaired capacity to generate peripherally induced regulatory T cells (pTreg) through an IL-6 regulated pathway, while CD4+ T cells co-cultured with aged macrophages demonstrated increased proliferation. Our study establishes aging as a key regulator of the effector immune response in uveitis. Regulatory T cells, specifically pTreg, are essential for resolving inflammation in uveitis and an impaired ability to induce pTreg led to a sustained, chronic inflammatory uveitis phenotype in old mice, thereby linking immunosenescence to persistent neuroinflammation. These findings highlight potential therapeutic avenues for vision-threatening uveitis, especially in older patients.

immunology↗

bioRxiv2025

MicroRNA-34a suppresses KLF2 to promote pathological angiogenesis through the CXCR4/CXCL12 pathway in age-related macular degeneration

Age-related macular degeneration (AMD), characterized by pathologic choroidal neovascularization (CNV), is a leading cause of vision loss in the elderly. Vascular endothelial growth factor A (VEGFa) antagonists can prevent acute vision loss, but high treatment burden and loss of efficacy with chronic therapy highlight the need to explore alternative mechanisms. Recently, microRNA-34a (miR-34a) has emerged as a key regulator in aging and age-related diseases, but its role in neovascular AMD is unclear. In an injury-induced murine CNV model, we discovered miR-34a promoted pathological angiogenesis, without altering expression of Vegfa or its receptor Kdr, the canonical regulators of CNV. Mechanistically, miR-34a directly targets and inhibits the transcription factor KLF2 thereby upregulating the pro-angiogenic factors CXCR4 and CXCL12. Finally, we show miR-34a exacerbates CNV in aged mice and is expressed in CNV lesions excised from wet AMD patients. These findings establish a causal link between the age-related miR-34a and neovascularization in AMD. TeaserIdentification of a molecular mechanism involved in the pathogenesis of a prevalent and debilitating age-related ocular disease.

molecular biology↗

bioRxiv2020

SARM1 depletion rescues NMNAT1 dependent photoreceptor cell death and retinal degeneration.

Leber congenital amaurosis type 9 is an autosomal recessive retinopathy caused by mutations of the NAD+ synthesis enzyme NMNAT1. Despite the ubiquitous expression of NMNAT1, patients do not manifest pathologies other than retinal degeneration. Here we demonstrate that widespread NMNAT1 depletion in adult mice mirrors the human pathology, with selective loss of photoreceptors highlighting the exquisite vulnerability of these cells to NMNAT1 loss. Conditional deletion demonstrates that NMNAT1 is required within the photoreceptor. Mechanistically, loss of NMNAT1 activates the NADase SARM1, the central executioner of axon degeneration, to trigger photoreceptor death and vision loss. Hence, the essential function of NMNAT1 in photoreceptors is to inhibit SARM1, highlighting an unexpected shared mechanism between axonal degeneration and photoreceptor neurodegeneration. These results define a novel SARM1-dependent photoreceptor cell death pathway and identifies SARM1 as a therapeutic candidate for retinopathies.

neuroscience↗