The retina as a window to early dysfunctions of Alzheimer's disease following studies with a 5xFAD mouse model

Criscuolo, Chiara; Cerri, Elisa; Fabiani, Carlotta; Capsoni, Simona; Cattaneo, Antonino; Domenici, Luciano

doi:10.1016/j.neurobiolaging.2018.03.017

Cited by 55 publications

(47 citation statements)

References 61 publications

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“…Functionally, 5xFAD mice show attenuation of the ganglion cell dominated pSTR, with no changes to bipolar, amacrine and photoreceptor mediated responses at 6 months (Figures 5, 6), consistent with the observed structural change in the inner retina and inner retinal amyloid deposits. In comparison with the literature, our findings were most consistent with other studies employing retinal ganglion cell measures in APP/PS1 (Gupta et al, 2016) and 5xFAD (Criscuolo et al, 2018). These ERG deficits corroborate previous reports of ganglion cell dysfunction in clinical cohorts with AD (Katz et al, 1989;Trick et al, 1989;Parisi et al, 2001;Krasodomska et al, 2010;Sartucci et al, 2010).…”

Section: Discussionsupporting

confidence: 92%

“…The work of Criscuolo et al (2018) indicates the 5xFAD model may be a useful one to study vision changes which recapitulate human AD as functional measures indicate that retinal ganglion cell derived pattern ERG declines faster than middle/outer retinal full field ERG responses. We extend this work in 5xFAD mice by studying whether inner retinal functional changes in these mice are mirrored by structural changes with increasing age.…”

Section: Introductionmentioning

confidence: 99%

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Retinal Functional and Structural Changes in the 5xFAD Mouse Model of Alzheimer’s Disease

Lim

et al. 2020

Front. Neurosci.

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Alzheimer's disease is characterized by the aberrant deposition of protein in the brain and is the leading cause of dementia worldwide. Increasingly, there have been reports of the presence of these protein hallmarks in the retina. In this study, we assayed the retina of 5xFAD mice, a transgenic model of amyloid deposition known to exhibit dementia-like symptoms with age. Using OCT, we found that the retinal nerve fiber layer was thinner in 5xFAD at 6, 12, and 17 months of age compared with wild-type littermates, but the inner plexiform layer was thicker at 6 months old. Retinal function showed reduced ganglion cell responses to light in 5xFAD at 6, 12, and 17 months of age. This functional loss was observed in the outer retina at 17 months of age but not in younger mice. We showed using immunohistochemistry and ELISA that soluble and insoluble amyloid was present in the retina and brain at all ages. In conclusion, we report that amyloid is present in brain and retina of 5xFAD mice and that the pattern of neuronal dysfunction occurs in the inner retina at the early ages and progresses to encompass the outer retina with age. This implies that the inner retina is more sensitive to amyloid changes in early disease and that the outer retina is also affected with disease progression.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Retinal Functional and Structural Changes in the 5xFAD Mouse Model of Alzheimer’s Disease

Lim

et al. 2020

Front. Neurosci.

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“…In the sporadic O. degus model of AD, Aβ deposition appears to be progressive, accumulating first in the GCL, NFL, INL and photoreceptors (Chang et al, 2020). Whole Increased APP, Aβ, Aβ 42 toxicity Finelli et al, 2004;Greeve et al, 2004;Carmine-Simmen et al, 2009;Cutler et al, 2015 Mouse Tg2576, hTgAPP tg/tg , APP SWE /PS1 E9 , APP SWE /PS1 M146L/L286V , 3xTg, 5xFAD, Tg-SwDI Increased APP, Aβ deposits, Aβ 42 , Aβ 40 , vascular Aβ, Aβ oligomers Ning et al, 2008;Dutescu et al, 2009;Liu et al, 2009;Perez et al, 2009;Alexandrov et al, 2011;Koronyo-Hamaoui et al, 2011;Koronyo et al, 2012;Williams et al, 2013;Yang et al, 2013;Zhao et al, 2013;Edwards et al, 2014;He et al, 2014;Park et al, 2014;Gao et al, 2015;More and Vince, 2015;Parthasarathy et al, 2015;Pogue et al, 2015;Gupta et al, 2016;Oliveira-Souza et al, 2017;Criscuolo et al, 2018;Hadoux et al, 2019;Habiba et al, 2020;Sidiqi et al, 2020 O. degus Spontaneous Increased APP, Aβ, Aβ oligomers Inestrosa et al, 2005;Ardiles et al, 2012;Du et al, 2015 Rat TgF344-AD Increased Aβ Tsai et al, 2014 NFT or pTau related Drosophila hTau Accumulation of pTau Grammenoudi et al, 2006;Chouhan et al, 2016 Mouse Tg2576, APP SWE /PS1 E9 , APP SWE /PS1 M146L/L286V , 3xTg, P301S, rTg4510…”

Section: Alzheimer's Disease Hallmarks In the Retina Of Animal Modelsmentioning

confidence: 99%

Alzheimer’s Retinopathy: Seeing Disease in the Eyes

et al. 2020

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The neurosensory retina emerges as a prominent site of Alzheimer's disease (AD) pathology. As a CNS extension of the brain, the neuro retina is easily accessible for noninvasive, high-resolution imaging. Studies have shown that along with cognitive decline, patients with mild cognitive impairment (MCI) and AD often suffer from visual impairments, abnormal electroretinogram patterns, and circadian rhythm disturbances that can, at least in part, be attributed to retinal damage. Over a decade ago, our group identified the main pathological hallmark of AD, amyloid β-protein (Aβ) plaques, in the retina of patients including early-stage clinical cases. Subsequent histological, biochemical and in vivo retinal imaging studies in animal models and in humans corroborated these findings and further revealed other signs of AD neuropathology in the retina. Among these signs, hyperphosphorylated tau, neuronal degeneration, retinal thinning, vascular abnormalities and gliosis were documented. Further, linear correlations between the severity of retinal and brain Aβ concentrations and plaque pathology were described. More recently, extensive retinal pericyte loss along with vascular platelet-derived growth factor receptor-β deficiency were discovered in postmortem retinas of MCI and AD patients. This progressive loss was closely associated with increased retinal vascular amyloidosis and predicted cerebral amyloid angiopathy scores. These studies brought excitement to the field of retinal exploration in AD. Indeed, many questions still remain open, such as queries related to the temporal progression of AD-related pathology in the retina compared to the brain, the relations between retinal and cerebral changes and whether retinal signs can predict cognitive decline. The extent to which AD affects the retina, including the susceptibility of certain topographical regions and cell types, is currently under intense investigation. Advances in retinal amyloid imaging, hyperspectral imaging, optical coherence tomography, and OCT-angiography encourage the use of such modalities to achieve more accurate, patient-and user-friendly, noninvasive detection and monitoring of AD. In this review, we summarize the current status in the field while addressing the many unknowns regarding Alzheimer's retinopathy.

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“…Numerous recent studies reported the presence of β -amyloid plaques in the retina of patients, opening the possibility of detecting AD though simple noninvasive eye scans [ 34 – 38 ]. In a parallel way, other studies revealed degenerative changes and retinal neuron damage in the retina/eye of AD animal models [ 39 – 43 ]. Consequently, various laboratories are trying to explore this approach, developing optical retinal imaging platforms capable to detect β -amyloid plaques in the retina of AD subjects [ 38 , 44 – 48 ].…”

Section: Introductionmentioning

confidence: 79%

Ocular Manifestations of Alzheimer’s and Other Neurodegenerative Diseases: The Prospect of the Eye as a Tool for the Early Diagnosis of Alzheimer’s Disease

Colligris

Lara

Colligris

et al. 2018

Journal of Ophthalmology

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Dementia, including Alzheimer's disease (AD), is a major disorder, leading to several ocular manifestations amongst the elderly population. These visual disorders may be due to retinal nerve degenerative changes, including nerve fibre layer thinning, degeneration of retinal ganglion cells, and changes to vascular parameters. There is no cure for Alzheimer's, but medicines can slow down the development of many of the classic symptoms, such as loss of memory and communication skills, mood swings, and depression. The disease diagnosis is difficult, and it is only possible through PET scans of the brain, detecting evidence of the accumulation of amyloid and tau. PET is expensive and invasive, requiring the injection of radioactive tracers, which bind with these proteins and glow during scanning. Recently, scientists developed promising eye-scan techniques that may detect Alzheimer's disease at its earliest stage, before major symptoms appear, leading to improved management of the disease symptoms. In this review, we are discussing the visual abnormalities of Alzheimer's and other neurodegenerative diseases, focused on ocular functional-visual-structural biomarkers, retinal pathology, and potential novel diagnostic tools.

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The retina as a window to early dysfunctions of Alzheimer's disease following studies with a 5xFAD mouse model

Cited by 55 publications

References 61 publications

Retinal Functional and Structural Changes in the 5xFAD Mouse Model of Alzheimer’s Disease

Retinal Functional and Structural Changes in the 5xFAD Mouse Model of Alzheimer’s Disease

Alzheimer’s Retinopathy: Seeing Disease in the Eyes

Ocular Manifestations of Alzheimer’s and Other Neurodegenerative Diseases: The Prospect of the Eye as a Tool for the Early Diagnosis of Alzheimer’s Disease

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