Parallels between retinal and brain pathology and response to immunotherapy in old, late‐stage Alzheimer's disease mouse models

Doustar, Jonah; Rentsendorj, Altan; Torbati, Tania; Regis, Giovanna C.; Fuchs, Dieu Trang; Sheyn, Julia; Mirzaei, Nazanin; Graham, Stuart L.; Shah, Prediman K.; Mastali, Mitra; Eyk, Jennifer E. Van; Black, Keith L.; Gupta, Vivek; Mirzaei, Mehdi; Koronyo, Yosef; Koronyo‐Hamaoui, Maya

doi:10.1111/acel.13246

Cited by 37 publications

(36 citation statements)

References 134 publications

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“…In humans, a wide range of visual disturbances have been reported in MCI and AD patients, including problems with color vision and contrast sensitivity, which could be attributed to AD pathology in the retina 11,33,[45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61] . We and other groups have previously shown that the same molecular hallmarks of the AD brain occur in the retina of AD animal models 6,33 and that they can be detected in parallel or prior to their detection in the brain 9,14,15,38,41 . Here, we report alternation deficits as early as 8.5 months in AD + mice, months before cognitive deficits could be detected.…”

Section: Discussionmentioning

confidence: 89%

“…Specifically, the retina of AD patients exhibits neuronal and pericyte cell loss along with retinal manifestation of AD pathological hallmarks—amyloid β-protein (Aβ) plaques and hyperphosphorylated tau (p-Tau) 9 – 13 , 16 – 27 . Similarly, numerous studies examining the retina of sporadic and transgenic animal models of AD have reported the existence of Aβ deposits and tauopathy that are linked with inflammation and neurodegeneration 9 , 14 , 15 , 28 – 41 .…”

Section: Introductionmentioning

confidence: 98%

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Color and contrast vision in mouse models of aging and Alzheimer’s disease using a novel visual-stimuli four-arm maze

Vit

Fuchs

Angel

et al. 2021

Sci Rep

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We introduce a novel visual-stimuli four-arm maze (ViS4M) equipped with spectrally- and intensity-controlled LED emitters and dynamic grayscale objects that relies on innate exploratory behavior to assess color and contrast vision in mice. Its application to detect visual impairments during normal aging and over the course of Alzheimer’s disease (AD) is evaluated in wild-type (WT) and transgenic APPSWE/PS1∆E9 murine models of AD (AD+) across an array of irradiance, chromaticity, and contrast conditions. Substantial color and contrast-mode alternation deficits appear in AD+ mice at an age when hippocampal-based memory and learning is still intact. Profiling of timespan, entries and transition patterns between the different arms uncovers variable AD-associated impairments in contrast sensitivity and color discrimination, reminiscent of tritanomalous defects documented in AD patients. Transition deficits are found in aged WT mice in the absence of alternation decline. Overall, ViS4M is a versatile, controlled device to measure color and contrast-related vision in aged and diseased mice.

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Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 98%

Color and contrast vision in mouse models of aging and Alzheimer’s disease using a novel visual-stimuli four-arm maze

Vit

Fuchs

Angel

et al. 2021

Sci Rep

Self Cite

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“…Relevantly, post-mitotic neurons have reduced glycolytic capacity and, then, strongly rely for energy production on mitochondria which are largely abundant and crucial for the survival of in RGCs endowed with great metabolic demand [ 149 ]. An interesting study [ 150 ] has recently reported parallels between retinal and brain pathology and in response to immunotherapy with Glatiramer acetate, an FDA‐approved drug which promotes microglial-mediated Aβ clearance in old APPSWE/PS1∆E9 ADtg mice. In this study, paired brains and eyeballs were collected at the end of the last injection and processed for biochemical and morphological analyses.…”

Section: Discussionmentioning

confidence: 99%

Systemic delivery of a specific antibody targeting the pathological N-terminal truncated tau peptide reduces retinal degeneration in a mouse model of Alzheimer’s Disease

Latina

Giacovazzo

Cordella

et al. 2021

acta neuropathol commun

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Retina and optic nerve are sites of extra-cerebral manifestations of Alzheimer’s Disease (AD). Amyloid-β (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau protein are detected in eyes from AD patients and transgenic animals in correlation with inflammation, reduction of synapses, visual deficits, loss of retinal cells and nerve fiber. However, neither the pathological relevance of other post-translational tau modifications—such as truncation with generation of toxic fragments—nor the potential neuroprotective action induced by their in vivo clearance have been investigated in the context of AD retinal degeneration. We have recently developed a monoclonal tau antibody (12A12mAb) which selectively targets the neurotoxic 20–22 kDa NH2-derived peptide generated from pathological truncation at the N-terminal domain of tau without cross-reacting with its full-length normal protein. Previous studies have shown that 12A12mAb, when intravenously (i.v.)-injected into 6-month-old Tg2576 animals, markedly improves their AD-like, behavioural and neuropathological syndrome. By taking advantage of this well-established tau-directed immunization regimen, we found that 12A12mAb administration also exerts a beneficial action on biochemical, morphological and metabolic parameters (i.e. APP/Aβ processing, tau hyperphosphorylation, neuroinflammation, synaptic proteins, microtubule stability, mitochondria-based energy production, neuronal death) associated with ocular injury in the AD phenotype. These findings prospect translational implications in the AD field by: (1) showing for the first time that cleavage of tau takes part in several pathological changes occurring in vivo in affected retinas and vitreous bodies and that its deleterious effects are successfully antagonized by administration of the specific 12A12mAb; (2) shedding further insights on the tight connections between neurosensory retina and brain, in particular following tau-based immunotherapy. In our view, the parallel response we detected in this preclinical animal model, both in the eye and in the hippocampus, following i.v. 12A12mAb injection opens novel diagnostic and therapeutic avenues for the clinical management of cerebral and extracerebral AD signs in human beings.

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“…Additional studies would be necessary to determine if the thinning is due to Aβ accumulation [ 173 , 174 ]. When aging AD mice models were immunized with glatiramer acetate, the retinal and brain glutamine synthetase levels became comparable to healthy WT mice, which appeared to restore glutamate levels, reduce excitotoxicity, and reduce synaptic loss [ 175 ]. Similar effects were observed with high concentration dosing of α2ARA, which appeared to modulate excitotoxicity and decrease excessive glutamate at synaptic clefts, which may help explain its potential effect in mitigating glaucoma and neAMD progression [ 24 , 128 ].…”

Section: Treatment Approaches For Reducing Aβ Accumulationmentioning

confidence: 99%

Role of Retinal Amyloid-β in Neurodegenerative Diseases: Overlapping Mechanisms and Emerging Clinical Applications

Wang

Mao

2021

IJMS

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Amyloid-β (Aβ) accumulations have been identified in the retina for neurodegeneration-associated disorders like Alzheimer’s disease (AD), glaucoma, and age-related macular degeneration (AMD). Elevated retinal Aβ levels were associated with progressive retinal neurodegeneration, elevated cerebral Aβ accumulation, and increased disease severity with a decline in cognition and vision. Retinal Aβ accumulation and its pathological effects were demonstrated to occur prior to irreversible neurodegeneration, which highlights its potential in early disease detection and intervention. Using the retina as a model of the brain, recent studies have focused on characterizing retinal Aβ to determine its applicability for population-based screening of AD, which warrants a further understanding of how Aβ manifests between these disorders. While current treatments directly targeting Aβ accumulations have had limited results, continued exploration of Aβ-associated pathological pathways may yield new therapeutic targets for preserving cognition and vision. Here, we provide a review on the role of retinal Aβ manifestations in these distinct neurodegeneration-associated disorders. We also discuss the recent applications of retinal Aβ for AD screening and current clinical trial outcomes for Aβ-associated treatment approaches. Lastly, we explore potential future therapeutic targets based on overlapping mechanisms of pathophysiology in AD, glaucoma, and AMD.

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Parallels between retinal and brain pathology and response to immunotherapy in old, late‐stage Alzheimer's disease mouse models

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 37 publications

References 134 publications

Color and contrast vision in mouse models of aging and Alzheimer’s disease using a novel visual-stimuli four-arm maze

Color and contrast vision in mouse models of aging and Alzheimer’s disease using a novel visual-stimuli four-arm maze

Systemic delivery of a specific antibody targeting the pathological N-terminal truncated tau peptide reduces retinal degeneration in a mouse model of Alzheimer’s Disease

Role of Retinal Amyloid-β in Neurodegenerative Diseases: Overlapping Mechanisms and Emerging Clinical Applications

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