Department of Ophthalmology

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Browsing Department of Ophthalmology by Author "Abhyankar, Surabhi D."

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    BMAL1 Overexpression in Suprachiasmatic Nucleus Protects from Retinal Neurovascular Deficits in Diabetes
    (bioRxiv, 2025-02-06) Mahajan, Neha; Luo, Qianyi; Lukkes, Jodi; Abhyankar, Surabhi D.; Bhatwadekar, Ashay D.; Ophthalmology, School of Medicine
    The suprachiasmatic nucleus (SCN) regulates circadian rhythms and influences physiological and behavioral processes. Disruptions in circadian rhythms (CRD) are observed in type 2 diabetes (T2D), and importantly, CRD acts as an independent risk factor for T2D and its associated complications. BMAL1, a circadian clock gene, is vital for sustaining an optimal circadian rhythm and physiological function. However, the therapeutic potential of BMAL1 overexpression in the SCN to rectify the neurovascular deficits of T2D has yet to be investigated. In this study, db/db mice, a well-established model of T2D exhibiting arrhythmic behavior and the complications of diabetes, were injected stereotaxically with AAV8-Bmal1 or a control virus in the SCN to evaluate the protective effects of correcting the central clock on neurovascular deficits. Given the complex neurovascular network and the eye's unique accessibility as a transparent system, ocular complications were selected as a model to examine the neuronal functional, behavioral, and vascular benefits of correcting the central clock. BMAL1 overexpression normalized the circadian rhythms, as demonstrated by improvements in the free-running period. The retinal neuronal function improved on electroretinogram, along with optomotor behavior and visual acuity enhancements. Retinal vascular deficits were also significantly reduced. Notably, our approach helped decrease fat content in genetically predisposed obese animals. Since the SCN is known to regulate hepatic glucose production via sympathetic mechanisms, glycemic control, and pyruvate tolerance tests were conducted. Systemically, we observed improved glucose homeostasis in BMAL1-overexpressing mice alongside a substantial reduction in hepatic gluconeogenesis. BMAL1 overexpression lowered plasma norepinephrine and liver TH levels, indicating a protective regulation of adrenergic signaling. Thus, this study underscores the therapeutic potential of targeting circadian clock genes like BMAL1 in the SCN to alleviate metabolic and neurovascular deficits associated with T2D. Our research offers a compelling framework for integrating circadian rhythms into managing diabetes and its complications.
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    Retinal dysfunction in APOE4 knock‐in mouse model of Alzheimer's disease
    (Wiley, 2025) Abhyankar, Surabhi D.; Luo, Qianyi; Hartman, Gabriella D.; Mahajan, Neha; Corson, Timothy W.; Oblak, Adrian L.; Lamb, Bruce T.; Bhatwadekar, Ashay D.; Ophthalmology, School of Medicine
    Introduction: Late-onset Alzheimer's Disease (LOAD) is the predominant form of Alzheimer's disease (AD), and apolipoprotein E (APOE) ε4 is a strong genetic risk factor for LOAD. As an integral part of the central nervous system, the retina displays a variety of abnormalities in LOAD. Our study is focused on age-dependent retinal impairments in humanized APOE4-knock-in (KI) and APOE3-KI mice developed by the Model Organism Development and Evaluation for Late-Onset Alzheimer's Disease (MODEL-AD) consortium. Methods: All the experiments were performed on 52- to 57-week-old mice. The retina was assessed by optical coherence tomography, fundoscopy, fluorescein angiography, electroretinography, optomotor response, gliosis, and neuroinflammation. mRNA sequencing was performed to find molecular pathways. Results: APOE4-KI mice showed impaired retinal structure, vasculature, function, vision, increased gliosis and neuroinflammation, and downregulation of synaptogenesis. Discussion: The APOE ε4 allele is associated with increased susceptibility to retinal degeneration compared to the APOE ε3 allele. Highlights: Apolipoprotein E (APOE)4 mice exhibit structural and functional deficits of the retina. The retinal defects in APOE4 mice are attributed to increased neuroinflammation. APOE4 mice show a unique retinal transcriptome, yet with key brain similarities. The retina offers a non-invasive biomarker for the detection and monitoring of Alzheimer's disease.