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Low-dose anti-HIV drug efavirenz mitigates retinal vascular lesions in a mouse model of Alzheimer's disease

ABSTRACT: A small dose of the anti-HIV drug efavirenz (EFV) was previously discovered to activate CYP46A1, a cholesterol-eliminating enzyme in the brain, and mitigate some of the manifestation of Alzheimer’s disease in 5XFAD mice. Herein, we investigated the retina of these animals, which were found to have genetically determined retinal vascular lesions associated with deposits within the retinal pigment epithelium and subretinal space. We established that EFV treatment activated CYP46A1 in the retina, enhanced retinal cholesterol turnover, and diminished the lesion frequency >5-fold. In addition, the treatment mitigated fluorescein leakage from the aberrant blood vessels, deposit size, activation of retinal macrophages/microglia, and focal accumulations of amyloid b plaques, unesterified cholesterol, and Oil Red O-positive lipids. Studies of retinal transcriptomics and proteomics identified biological processes enriched with differentially expressed genes and proteins. We discuss the mechanisms of the beneficial EFV effects on the retinal phenotype of 5XFAD mice. As EFV is an FDA-approved drug, and we already tested the safety of small-dose EFV in patients with Alzheimer’s disease, our data support further clinical investigation of this drug in subjects with retinal vascular lesions or neovascular age-related macular degeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE199867 | GEO | 2022/04/27

REPOSITORIES: GEO

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Low-dose anti-HIV drug efavirenz mitigates retinal vascular lesions in a mouse model of Alzheimer’s disease

Project description:A small dose of the anti-HIV drug efavirenz (EFV) was previously discovered to activate CYP46A1, a cholesterol-eliminating enzyme in the brain, and mitigate some of the manifestation of Alzheimer’s disease in 5XFAD mice(a mouse model foe Alzheimers disease. Herein, we investigated the retina of these animals, which were found to have genetically determined retinal vascular lesions associated with deposits within the retinal pigment epithelium and sub retinal space.. Thus gain an unbiased insight into the processes in the retina that could be to affected by efavirenz treatment, the proteomic approach was used to compare the retinas of efavirenz -treated and control 5XFAD mice.

2022-05-27 | PXD033037 | Pride

Cholesterol 24-hydroxylase at the choroid plexus restrains local inflammation and protects overall brain function

Project description:Inflammation of the choroid plexus (CP), the interface between blood and cerebrospinal fluid, impacts the brain in aging and disease. Here, we report that the CP epithelium in mice and humans expresses CYP46A1 (cholesterol 24-hydroxylase), a brain-specific enzyme. CP CYP46A1 expression levels were found to be reduced in a mouse model of amyloidosis (5xFAD) and in aged mice, as well as in postmortem samples from COVID-19 victims. Bulk RNA-sequencing revealed that the CP epithelium responds in vitro to the enzymatic product of CYP46A1, 24(S)-hydroxycholesterol, by downregulating inflammatory transcriptomic signatures that we found in silico to be expressed in the CP across multiple neurological conditions. Moreover, the inflammatory cytokine TNF-α reduced CP Cyp46a1 expression, both in vitro and ex vivo, whereas Cyp46a1 overexpression attenuated the CP response to TNF-α. We propose that CYP46A1 plays a key regulatory role in CP homeostasis, with implications for various CNS pathologies, including sequelae of viral infections.

2023-08-16 | GSE200318 | GEO

Transcriptomic effects of long-term pantethine treatment in the mouse Alzheimer's disease 5XFAD model

Project description:Pantethine, an anti-cholesterol drug, was shown to inhibit the Ab (amyloid beta) peptide-induced expression of IL-1b in primary culture astrocytes derived from either untreated Ab-treated and untreated 5XFAD or Ab-treated WT. These observations prompted us to investigate the effects of pantethine at the transcriptomic level in the mouse AD model.

2018-07-15 | E-MTAB-6772 | biostudies-arrayexpress

Endothelin2 signaling in the neural retina promotes the endothelial tip cell state and inhibits angiogenesis

Project description:Endothelin signaling is required for neural crest migration and homeostatic regulation of blood pressure. Here we report that constitutive over-expression of Endothelin-2 (Edn2) in the mouse retina perturbs vascular development by inhibiting endothelial cell (EC) migration across the retinal surface and subsequent EC invasion into the retina. Developing endothelial cells exist in one of two states: tip cells at the growing front, and stalk cells in the vascular plexus behind the front. This division of endothelial cell states is one of the central organizing principle of angiogenesis. In the developing retina, Edn2 over-expression leads to over-production of endothelial tip cells by both morphologic and molecular criteria. Spatially localized over-expression of Edn2 produces a correspondingly localized endothelial response. Edn2 over-expression in the early embryo inhibits vascular development at mid-gestation, but Edn2 over-expression in developing skin and brain has no discernable effect on vascular structure. Inhibition of retinal angiogenesis by Edn2 requires expression of Endothelin receptor A (Ednra) but not Ednrb in the neural retina. Taken together, these observations imply that the neural retina responds to Edn2 by synthesizing one or more factors that promote the endothelial tip cell state and inhibit angiogenesis. The response to Edn2 is sufficiently potent that it over-rides the activities of other homeostatic regulators of angiogenesis, such as vascular endothelial growth factor. Z/Edn2 females were crossed to Six3-Cre; Six3-Cre males. Postnatal P8 pups were genotyped for the Z/Edn2 allele by detection of Laz-Z activity in tail clips. Retinas from 2 - 3 pups were pooled for each data point.

2014-01-01 | E-GEOD-50059 | biostudies-arrayexpress

Modifications in Retinal Microvascularization With Targeted Anti-angiogenic Therapy in Colorectal Cancer

Project description:Retinal microvascularization can provide important informations to systemic vascular phenomena. The non-invasive quantitative description of the retinal vascularization is now possible by performing OCT-angiography and their image analysis software (vascular density and retinal perfusion). Systemic microvacular changes during the establishment of oncological treatment by targeted antiangiogenic therapy are little described in the literature. The objective of this pilot study is to describe the evolution of the retinal vascular density of patients with antiangiogenic drugs. In addition, the evolution of the retinal vascular density of patients on antiangiogenic drugs will study as a function of the response to the treatment and the toxicity of these treatments.

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The transcriptional response to Norrin/Fz4 signaling

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2014-06-05 | E-GEOD-56461 | biostudies-arrayexpress

RNA analysis of the circadian rhythm of choroidal neovascularization

Project description:Many diseases that affect the heart, brain, and even the eyes originate from vascular pathology, emphasizing the role of vascular regulation. In age-related macular degeneration (AMD), excessive growth of abnormal blood vessels in the eye (choroidal neovascularization) ultimately leads to detachment of retinal pigment epithelium and decreased vision, indicating the importance of choroidal neovascularization in the treatment of age-related diseases. The circadian clock in the mammalian retina regulates various retinal functions, enabling the retina to adapt to the light dark cycle. Emerging evidence suggests a link between circadian clock and retinopathy, but the causal relationship has not yet been determined.

2024-10-09 | GSE253949 | GEO

Extensive Sub-RPE Complement Deposition in a Nonhuman Primate Model of Early Stage Diabetic Retinopathy

Project description:Purpose: This study aims to reveal retinal abnormities in a spontaneous diabetic nonhuman primate (NHP) model and explore the mechanism of featured injuries. Methods: Twenty-eight cynomolgus monkeys were identified to suffer from spontaneous Type 2 diabetes from a colony of more than eight hundred aged monkeys and twenty-six age-matched ones were used as controls. Their blood biochemistry profiles were determined and the retinal changes were examined by multimodal imaging, hematoxylin-eosin (H&E) staining and immunofluorescence. Retinal pigment epithelium (RPE) cells were isolated and determined by RNA-sequencing and computational analyses. Results: Diabetic monkeys were characterized by early vascular and neural damage in the retina and dyslipidemia. The typical acellular capillaries and pericyte ghost were found in the diabetic retina, which also exhibited reduced retinal nerve fiber layer (RNFL) thickness compared to the controls. Of note, distinct sub-RPE drusenoid lesions were extensively observed in these diabetic monkeys and complements deposition including C3 and C5b-9 were accumulated in these lesions. The RNA-seq data of RPE cells showed complement activation, AGE/RAGE activation and 18 inflammatory response at the setting of diabetes. Consistently, the plasma levels of C3 and C4 were also increased in the diabetic monkeys. Conclusions: The spontaneous Type 2 diabetic cynomolgus monkeys featured with early-stage retinopathy including not only typical vascular and neural damage, but also a distinct sub-RPE deposition. The complement activation and metabolic stress of RPE cells in response to hyperglycemia might contribute to the deposition, revealing an unrecognized role of RPE cells in the early-stage pathological process of diabetic retinopathy (DR).

2021-03-31 | GSE160617 | GEO

FACS-array profiling in retinal endothelial cells from living mouse retinas without pericyte coverage

Project description:Pericytes confer vascular stability in the retina, and the loss of pericytes can cause the blood-retina barrier breakdown seen in diabetic retinopathy. To identify endothelial-specific genes expressed in pericyte-deprived retinal vessels, we purified genetically labeled endothelial cells from Tie2-GFP transgenic mice treated with neutralizing antibody against PDGFRb (APB5) and performed gene expression profiling using DNA microarray. To find out endothelial-specific genes associated with the loss of pericyte coverage, the comparison of microarray data was carried out between retinal endothelial cells (data from GSE27238) and APB5-treated retinal endothelial cells.

2017-01-01 | GSE86819 | GEO

Oxygen-induced pathological angiogenesis promotes intense lipid synthesis and remodeling in the retina

Project description:<p>The retina is a notable tissue with high metabolic needs which relies on specialized vascular networks to protect the neural retina while maintaining constant supplies of oxygen, nutrients and dietary essential fatty acids. Here we analyzed the lipidome of the mouse retina under healthy and pathological angiogenesis using the oxygen-induced retinopathy model. By matching lipid profiles to changes in mRNA transcriptome, we identified a lipid signature showing that pathological angiogenesis leads to intense lipid remodeling favoring pathways for neutral lipid synthesis, cholesterol import/export and lipid droplet formation. Noteworthy, it also shows profound changes in pathways for long-chain fatty acid production, vital for retina homeostasis. The net result is accumulation of large quantities of mead acid, a marker of essential fatty acid deficiency, and a potential marker for retinopathy severity. Thus, our lipid signature might contribute to better understand diseases of the retina that lead to vision impairment or blindness.</p>

2023-05-09 | MTBLS6965 | MetaboLights

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