Neuroinflammatory Processes, A1 Astrocyte Activation and Protein Aggregation in the Retina of Alzheimer’s Disease Patients, Possible Biomarkers for Early Diagnosis

Grimaldi, Alfonso; Pediconi, Natalia; Oieni, Francesca; Pizzarelli, Rocco; Rosito, Maria; Giubettini, Maria; Santini, Tiziana; Limatola, Cristina; Ruocco, G.; Ragozzino, Davide; Angelantonio, Silvia Di

doi:10.3389/fnins.2019.00925

Cited by 110 publications

(158 citation statements)

References 68 publications

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“…A quantitative histological analysis of whole-mount retinas in a subset of confirmed AD patients compared to age-and sex-matched cognitively normal controls revealed a significant 4.7-fold increase in Aβ 42 -containing retinal plaque burden in patients ( Figure 2D; Koronyo et al, 2017). Another group, using a sample of retinas isolated from 10 neuropathologically and clinically confirmed AD and 10 control patients, demonstrated a significant 2.7-fold increase in the number of retinal Aβ 42 plaques that were also found to be larger in volume relative to deposits detected in normal control tissue (Grimaldi et al, 2019). Importantly, although retinal Aβ plaques are typically smaller in size compared to brain plaques, their burden in the retina significantly correlated with severity of plaque pathology in the brain (Figures 2E,F; Koronyo et al, 2017).…”

Section: Retinal Aβ Pathology In Alzheimer's Patientsmentioning

confidence: 93%

“…Intriguingly, CSF total tau and pTau-181 concentrations were shown to correlate with retinal changes measured by fluorescent lifetime ophthalmoscopy, a technique suggested to detect the metabolic alterations of tissue represented by fluorescence decay of endogenous fluorophores (Jentsch et al, 2015). Nevertheless, the co-localization of pTau (den Haan et al, 2018;Grimaldi et al, 2019) and sites of neuronal loss in the retina (Koronyo et al, 2017;Asanad et al, 2019b;Grimaldi et al, 2019) are indicative of similar physiological vulnerabilities to pTau accumulation in both the retina and brain.…”

Section: Retinal Tauopathy In Alzheimer's Patientsmentioning

confidence: 96%

“…This challenge emphasizes the necessity to standardize approaches for analyzing AD-related pathology across diverse topographical regions of the human retina. Indeed, following untraditional histological protocols developed by Koronyo and colleagues, three additional independent groups were able to detect Aβ deposits in the retina of confirmed AD patients (Tsai et al, 2014;den Haan et al, 2018;Grimaldi et al, 2019).…”

Section: Retinal Aβ Pathology In Alzheimer's Patientsmentioning

confidence: 99%

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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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Section: Retinal Aβ Pathology In Alzheimer's Patientsmentioning

confidence: 93%

Section: Retinal Tauopathy In Alzheimer's Patientsmentioning

confidence: 96%

Section: Retinal Aβ Pathology In Alzheimer's Patientsmentioning

confidence: 99%

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Alzheimer’s Retinopathy: Seeing Disease in the Eyes

et al. 2020

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“…AD is a chronic and progressive neurodegenerative disorder, which is accounted as the primary cause of dementia in the aging population [78,79]. At a cellular and molecular level, AD is characterized by extracellular amyloid-beta peptides aggregation, intracellular deposits of hyperphosphorylated TAU, neurodegeneration, and microglia and astrocyte activation in the brain and retina [80,81]. Up to now, no effective disease-modifying therapies are available for AD patients.…”

Section: Dmf Targets In Neurodegenerative Disordersmentioning

confidence: 99%

Exploring the Use of Dimethyl Fumarate as Microglia Modulator for Neurodegenerative Diseases Treatment

et al. 2020

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The maintenance of redox homeostasis in the brain is critical for the prevention of the development of neurodegenerative diseases. Drugs acting on brain redox balance can be promising for the treatment of neurodegeneration. For more than four decades, dimethyl fumarate (DMF) and other derivatives of fumaric acid ester compounds have been shown to mitigate a number of pathological mechanisms associated with psoriasis and relapsing forms of multiple sclerosis (MS). Recently, DMF has been shown to exert a neuroprotective effect on the central nervous system (CNS), possibly through the modulation of microglia detrimental actions, observed also in multiple brain injuries. In addition to the hypothesis that DMF is linked to the activation of NRF2 and NF-kB transcription factors, the neuroprotective action of DMF may be mediated by the activation of the glutathione (GSH) antioxidant pathway and the regulation of brain iron homeostasis. This review will focus on the role of DMF as an antioxidant modulator in microglia processes and on its mechanisms of action in the modulation of different pathways to attenuate neurodegenerative disease progression.

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“…Inflammation response caused by microglia plays a critical role in the pathogenesis of AMD [14,15]. Microglial cells are the major resident immune cells in the central nervous system (CNS) and the retina, displaying a few of distinctive features and profoundly being influenced by the local microenvironment [16].…”

Section: Introductionmentioning

confidence: 99%

Activated microglia-induced neuroinflammatory cytokines lead to photoreceptor apoptosis in age-related macular degeneration-like mice model

Gao

Shi

et al. 2020

Preprint

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Background Age-related macular degeneration (AMD) is mainly characterized by progressive deposits of drusen and photoreceptor apoptosis. Due to amyloid β (Aβ) is the main component of drusen, there is a great possibility that Aβ-induced activated microglia leads to inflammation, and plays a critical role in the pathogenesis of AMD. However, the relationship between activated microglia-mediated neuroinflammatory cytokines and photoreceptor apoptosis still remains unclarified. Results In this study, we demonstrated that subretinal injection of Aβ1−42 induced the microglia activation and increased inflammatory cytokines, gave rise to photoreceptor apoptosis in mice. Our results were verified in vitro by co-culture of Aβ1−42 activated primary microglia and photoreceptor cell line 661W, and we also performed that p38 MAPK signaling pathway was involved in Aβ1−42 induced microglia activation and inflammatory cytokines release. Conclusions Overall, our findings indicated that activated microglia-mediated neuroinflammatory cytokines contributed to photoreceptor apoptosis under the stimulation of Aβ1−42. Moreover, this study will provide a potential preventive and therapeutic approach for AMD treatment.

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Neuroinflammatory Processes, A1 Astrocyte Activation and Protein Aggregation in the Retina of Alzheimer’s Disease Patients, Possible Biomarkers for Early Diagnosis

Cited by 110 publications

References 68 publications

Alzheimer’s Retinopathy: Seeing Disease in the Eyes

Alzheimer’s Retinopathy: Seeing Disease in the Eyes

Exploring the Use of Dimethyl Fumarate as Microglia Modulator for Neurodegenerative Diseases Treatment

Activated microglia-induced neuroinflammatory cytokines lead to photoreceptor apoptosis in age-related macular degeneration-like mice model

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