Inhibition of AMD-Like Pathology With a Neurotrophic Compound in Aged Rats and 3xTg-AD Mice

Liu, Yinghua; Wei, Wei; Baazaoui, Narjes; Liu, Fei; Iqbal, Khalid

doi:10.3389/fnagi.2019.00309

Cited by 11 publications

(7 citation statements)

References 94 publications

(136 reference statements)

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“…VDAC1 knockdown induced inward folds of the ONL associated with local retinal detachments and thinning of the INL. This pattern resembles rat retina aging [ 34 , 35 ], known as the rosette. Rosette formation is associated with changes in mitochondrial morphology [ 36 ], which causes dysregulation of mitochondrial processes [ 37 ].…”

Section: Discussionmentioning

confidence: 95%

VDAC1 regulates neuronal cell loss after retinal trauma injury by a mitochondria-independent pathway

et al. 2022

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The voltage-dependent anion channel 1 (VDAC1) was first described as a mitochondrial porin that mediates the flux of metabolites and ions, thereby integrating both cell survival and death signals. In the nervous system, the functional roles of VDAC1 remain poorly understood. Herein, the rat retina was employed to study VDAC1. First, it was observed that even subtle changes in VDAC1 levels affect neuronal survival, inducing severe alterations in the retinal morphology. We next examined the regulation of VDAC1 after traumatic retinal injury. After mechanical trauma, SOD1 translocates towards the nucleus, which is insufficient to contain the consequences of oxidative stress, as determined by the evaluation of protein carbonylation. Using in vitro models of oxidative stress and mechanical injury in primary retinal cell cultures, it was possible to determine that inhibition of VDAC1 oligomerization by 4′-diisothiocyano-2,2′-disulfonic acid stilbene (DIDS) rescues cell viability, impacting microglial cell activation. We next focused on the regulation of VDAC1 after retinal mechanical injury. VDAC1 was promptly upregulated 2 h after lesion in the plasma membrane and endoplasmic reticulum rather than in the mitochondria, and multimers of VDAC1 were assembled after lesion. DIDS intraocular application decreased apoptosis and prevented microglial polarization, which confirmed in vitro observations. Considering the role of microglia in neuroinflammation, multiplex evaluation of cytokines showed that DIDS application disorganized the inflammatory response 2 h after the lesion, matching the fast regulation of VDAC1. Taken together, data disclosed that fine regulation of VDAC1 influences neuronal survival, and pharmacological inhibition after trauma injury has neuroprotective effects. This protection may be attributed to the effects on VDAC1 abnormal accumulation in the plasma membrane, thereby controlling the activation of microglial cells. We concluded that VDAC1 is a putative therapeutic target in neuronal disorders since it integrates both death and survival cellular signaling.

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Section: Discussionmentioning

confidence: 95%

VDAC1 regulates neuronal cell loss after retinal trauma injury by a mitochondria-independent pathway

et al. 2022

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“…Aβ, an important component of drusen deposits, has long been considered a pathogenic molecule and potential therapy target to prevent or treat AMD ( 9 , 40 ). Aβ peptides are continuously metabolized by the sequential cleavage of APP, and the overexpression of APP could lead to the accumulation of Aβ ( 41 ).…”

Section: Discussionmentioning

confidence: 99%

(–)-Epicatechin Provides Neuroprotection in Sodium Iodate-Induced Retinal Degeneration

et al. 2022

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Oxidative stress, mitochondrial impairment, and pathological amyloid beta (Aβ) deposition are involved in the pathogenesis of dry age-related macular degeneration (AMD). The natural flavonoid (–)-epicatechin (EC) is known to be an antioxidant and neuroprotective compound. Whether EC plays a therapeutic role in AMD is unknown. In this work, we aimed to assess the efficacy and molecular mechanisms of EC against sodium iodate (NaIO3)-induced retinal degeneration in C57BL/6 mice via bioinformatic, morphological, and functional methods. We demonstrated that EC had no toxic effects on the retina and could ameliorate retinal deformation and thinning. EC treatment prevented outer retinal degeneration, reduced drusen-like deposits, increased b-wave amplitude in electroretinography, blocked retinal gliosis, and increased the number and quality of mitochondria. Importantly, EC increased the protein expression of OPA1 and decreased the expression of PINK1, indicating the role of EC in mitochondrial fusion that impaired by NaIO3. Moreover, EC downregulated APP and TMEM97 levels, upregulated PGRMC1 levels, and reduced subretinal Aβ accumulation. This study illustrated that EC, which may become a promising therapeutic strategy for AMD, prevented NaIO3-induced retinal degeneration, and this improvement may be associated with the mitochondrial quality control and the TMEM97/PGRMC1/Aβ signaling pathway.

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“…microbiota or the gut epithelium. Metabolites can have neuroprotective trophic action (Liu, 2018) promoting neuron survival and plasticity in both the ENS and the CNS (Figure 1) (Liu et al, 2019). In a study conducted by (Vidal-Martínez et al, 2016) and colleagues, transgenic mice overexpressing mutant human α-synuclein developed PD-like enteric neuropathology.…”

Section: The Gi Tract and Ens Interactionsmentioning

confidence: 99%

Towards early detection of neurodegenerative diseases: A gut feeling

Makdissi

Parsons

Cara

2023

Front. Cell Dev. Biol.

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The gastrointestinal tract communicates with the nervous system through a bidirectional network of signaling pathways called the gut-brain axis, which consists of multiple connections, including the enteric nervous system, the vagus nerve, the immune system, endocrine signals, the microbiota, and its metabolites. Alteration of communications in the gut-brain axis is emerging as an overlooked cause of neuroinflammation. Neuroinflammation is a common feature of the pathogenic mechanisms involved in various neurodegenerative diseases (NDs) that are incurable and debilitating conditions resulting in progressive degeneration and death of neurons, such as in Alzheimer and Parkinson diseases. NDs are a leading cause of global death and disability, and the incidences are expected to increase in the following decades if prevention strategies and successful treatment remain elusive. To date, the etiology of NDs is unclear due to the complexity of the mechanisms of diseases involving genetic and environmental factors, including diet and microbiota. Emerging evidence suggests that changes in diet, alteration of the microbiota, and deregulation of metabolism in the intestinal epithelium influence the inflammatory status of the neurons linked to disease insurgence and progression. This review will describe the leading players of the so-called diet-microbiota-gut-brain (DMGB) axis in the context of NDs. We will report recent findings from studies in model organisms such as rodents and fruit flies that support the role of diets, commensals, and intestinal epithelial functions as an overlooked primary regulator of brain health. We will finish discussing the pivotal role of metabolisms of cellular organelles such as mitochondria and peroxisomes in maintaining the DMGB axis and how alteration of the latter can be used as early disease makers and novel therapeutic targets.

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Inhibition of AMD-Like Pathology With a Neurotrophic Compound in Aged Rats and 3xTg-AD Mice

Cited by 11 publications

References 94 publications

VDAC1 regulates neuronal cell loss after retinal trauma injury by a mitochondria-independent pathway

VDAC1 regulates neuronal cell loss after retinal trauma injury by a mitochondria-independent pathway

(–)-Epicatechin Provides Neuroprotection in Sodium Iodate-Induced Retinal Degeneration

Towards early detection of neurodegenerative diseases: A gut feeling

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