Retinal ganglion cell loss and gliosis in the retinofugal projection following intravitreal exposure to amyloid-beta

Simons, Emily; Smith, Matthew A.; Crish, Samuel D.

doi:10.1016/j.nbd.2020.105146

Cited by 14 publications

(14 citation statements)

References 87 publications

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“…Two structured illumination systems using 20×/0.8, 63×/1.4, and 150×/1.35 NA Plan-Apochromat objectives (Zeiss, Jena, Germany); all ran from the Zen operating software equipped with deconvolution and extended-depth-of-field modules. For retina imagining, multi-frame z-stacked acquisition was used to create a montage image composite of the entire retinal surface ( Simons et al, 2021 ). For the optic nerve, optical sections (0.3 μm) through longitudinal sections were collected using the Apotome 2.…”

Section: Methodsmentioning

confidence: 99%

Absence of Cytochrome P450-1b1 Increases Susceptibility of Pressure-Induced Axonopathy in the Murine Retinal Projection

Amirmokhtari¹,

Foresi²,

Dewan³

et al. 2021

Front. Cell Dev. Biol.

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Mutations in the cytochrome P450-1B1 (Cyp1b1) gene is a common genetic predisposition associated with various human glaucomas, most prominently in primary congenital glaucoma (PCG). The role of Cyp1b1 in the eye is largely unknown, however, its absence appears to drive the maldevelopment of anterior eye structures responsible for aqueous fluid drainage in murine models. Nevertheless, vision loss in glaucoma ultimately results from the structural and functional loss of retinal ganglion cells (RGCs). Cyp1b1’s influence in the development and support of retinal ganglion cell structure and function under normal conditions or during stress, such as elevated ocular pressure; the most common risk factor in glaucoma, remains grossly unknown. Thus, to determine the role of Cyp1b1 in normal retinal projection development we first assessed the strucutrual integrity of RGCs in the retina, optic nerve, and superior colliculus in un-manipulated (naïve) Cyp1b1-knockout (Cyp1b1–/–) mice. In addition, in a separate cohort of Cyp1b1–/– and wildtype mice, we elevated and maintained intraocular pressure (IOP) at glaucomatous levels for 5-weeks, after which we compared RGC density, node of Ranvier morphology, and axonal transport between the genotypes. Our results demonstrate that naïve Cyp1b1–/– mice develop an anatomically intact retinal projection absent of overt glaucomatous pathology. Following pressure elevation, Cyp1b1–/– accelerated degradation of axonal transport from the retina to the superior colliculus and altered morphology of the nodes of Ranvier and adjacent paranodes in the optic nerves. Together this data suggests the absence Cyp1b1 expression alone is insufficient to drive murine glaucomatous pathology, however, may increase the vulnerability of retinal axons to disease relevant elevations in IOP.

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Section: Methodsmentioning

confidence: 99%

Absence of Cytochrome P450-1b1 Increases Susceptibility of Pressure-Induced Axonopathy in the Murine Retinal Projection

Amirmokhtari¹,

Foresi²,

Dewan³

et al. 2021

Front. Cell Dev. Biol.

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“…As the eye, especially retinal tissue, represents "cerebral tissue" considering embryology, it is not remarkable that neurodegeneration and amyloid-β plaques were seen within the retina in AD patients (Whitehouse et al, 1981;Hinton et al, 1986;van de Nes et al, 2008). Degeneration of retinal ganglion cells (RGC) locally and retrograde degeneration of axons in the lateral geniculate body are two findings, being present in AD patients (Hinton et al, 1986;Sadun and Bassi, 1990;Braak and Braak, 1997;Simons et al, 2021). Even amyloid-ß can induce RGC loss within the retina itself (Simons et al, 2021).These neurodegenerative features were also observed in glaucomatous eyes (Lee et al, 2014;Russo et al, 2016;Schmidt et al, 2018;Kosior-Jarecka et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…Degeneration of retinal ganglion cells (RGC) locally and retrograde degeneration of axons in the lateral geniculate body are two findings, being present in AD patients (Hinton et al, 1986;Sadun and Bassi, 1990;Braak and Braak, 1997;Simons et al, 2021). Even amyloid-ß can induce RGC loss within the retina itself (Simons et al, 2021).These neurodegenerative features were also observed in glaucomatous eyes (Lee et al, 2014;Russo et al, 2016;Schmidt et al, 2018;Kosior-Jarecka et al, 2020). The diagnostic correlate of RGC loss can be seen in retinal nerve fiber layer thinning (RNFL) in vivo, visualized by magnet resonance tomography and optical coherence tomography (OCT) (Schmidt et al, 2018;Kosior-Jarecka et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

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Glaucoma and Alzheimer: Neurodegenerative disorders show an adrenergic dysbalance

Hohberger

Prüss

Mardin

et al. 2022

Preprint

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Glaucoma disease is characterized by an increased intraocular pressure (IOP), glaucomatous alterations of the optic disc and corresponding visual field defects. Even lowering the main risk factor IOP until an individual target level does not prevent this neurodegenerative disorder from proceeding. Several autoimmune mechanisms were discovered, partly showing a functionality. One of these autoimmune phenomena targets the beta2 adrenergic receptor (beta2-AR; i.e. agonistic autoantibodies; beta2-agAAb) and is linked to the elevated IOP and an impaired retinal microcirculation. As neurodegenerative disorder, Alzheimer Disease (AD) is postulated to share a common molecular mechanism with glaucoma. In the present study we investigated autoimmune phenomena targeting the beta2-AR in patients with AD. Sera of the patients were analyzed in a rat cardiomyocyte bioassay for the presence of functional autoantibodies against beta2-AR. In addition, different species of amyloid beta (A-beta) monomers were tested (A-beta1-14, A-beta10-25, A-beta10-37 A-beta1-40, A-beta1-42, A-beta28-40, and [Pyr]-beta3-42). Our results demonstrate that none of the short-chain A-beta (A-beta1-14, A-beta10-25, or A-beta28-40) showed any agonistic or inhibitory effect on beta2-AR. Contrary, long-chain [Pyr]-A-beta3-42, representing a major neurogenic plaque component, exerted an activation that was blocked by the beta2-AR antagonist ICI118.551 indicating that the effect was realized via the beta2-AR. Moreover, the long chain A-beta1-40, A-beta1-42, and A-beta10-37 yet not the short-chain A-beta peptides prevented the clenbuterol induced desensitization of the beta2-AR. In addition, we identified functional autoantibodies in the sera of AD patients, activating the beta2-AR like the beta2-agAAb found in patients with glaucoma. As autoimmune mechanisms were reportedly involved in the pathogenesis of glaucoma and Alzheimer Disease, we postulate that overstimulation of the beta2-AR pathway can induce an adrenergic overdrive, that may play an important role in the multifactorial interplay of neurodegenerative disorders.

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“…RGCs are metabolically demanding neurons that play a critical role relaying incoming sensory information from photoreceptors along their axons in the optic nerve to the visual information-processing center of the brain [44,45]. Thus, RGCs and their optic nerve pathways to the brain may serve as potential targets for pathological disruption of vision and as possible anatomical conduits for the spread of pathological proteins from the eye to the brain [46]. This is supported by data from early studies of postmortem human eye tissue from AD patients that showed the disease process was damaging RGCs-as evidenced by thinning of the nerve fiber layer [44,45,47], optic nerve degeneration [8], and overt loss of RGCs [48,49].…”

Section: Introductionmentioning

confidence: 99%

Alterations in Retinal Signaling Across Age and Sex in 3xTg Alzheimer’s Disease Mice

Frame

Schuller

Smith

et al. 2022

JAD

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Background: Visual disturbances often precede cognitive dysfunction in patients with Alzheimer’s disease (AD) and may coincide with early accumulation of amyloid-β (Aβ) protein in the retina. These findings have inspired critical research on in vivo ophthalmic Aβ imaging for disease biomarker detection but have not fully answered mechanistic questions on how retinal pathology affects visual signaling between the eye and brain. Objective: The goal of this study was to provide a functional and structural assessment of eye-brain communication between retinal ganglion cell (RGCs) and their primary projection target, the superior colliculus, in female and male 3xTg-AD mice across disease stages. Methods: Retinal electrophysiology, axonal transport, and immunofluorescence were used to determine RGC projection integrity, and retinal and collicular Aβ levels were assessed with advanced protein quantitation techniques. Results: 3xTg mice exhibited nuanced deficits in RGC electrical signaling, axonal transport, and synaptic integrity that exceeded normal age-related decrements in RGC function in age- and sex-matched healthy control mice. These deficits presented in sex-specific patterns among 3xTg mice, differing in the timing and severity of changes. Conclusion: These data support the premise that retinal Aβ is not just a benign biomarker in the eye, but may contribute to subtle, nuanced visual processing deficits. Such disruptions might enhance the biomarker potential of ocular amyloid and differentiate patients with incipient AD from patients experiencing normal age-related decrements in visual function.

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Retinal ganglion cell loss and gliosis in the retinofugal projection following intravitreal exposure to amyloid-beta

Cited by 14 publications

References 87 publications

Absence of Cytochrome P450-1b1 Increases Susceptibility of Pressure-Induced Axonopathy in the Murine Retinal Projection

Absence of Cytochrome P450-1b1 Increases Susceptibility of Pressure-Induced Axonopathy in the Murine Retinal Projection

Glaucoma and Alzheimer: Neurodegenerative disorders show an adrenergic dysbalance

Alterations in Retinal Signaling Across Age and Sex in 3xTg Alzheimer’s Disease Mice

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