Neuroprotective effect of memantine on the retinal ganglion cells of APPswe/PS1ΔE9 mice and its immunomodulatory mechanisms

Gao, Lixiong; Chen, Xi; Tang, Yongping; Zhao, Jinghui; Li, Qiyou; Fan, Xiaotang; Xu, Haiwei; Yin, Zheng

doi:10.1016/j.exer.2015.04.013

Cited by 47 publications

(42 citation statements)

References 52 publications

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“…In line with the above findings, numerous studies examining the retinas of sporadic and transgenic animal models of AD have reported Aβ deposits, vascular Aβ, pTau, and paired helical filament-tau (PHF-tau), often in association with RGC degeneration, local inflammation (i.e., microglial activation), and impairments of retinal structure and function (11,39,40,42,(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61). These studies, which included a variety of transgenic rat and mouse models, as well as the sporadic rodent model of AD, Octodon degus, demonstrated abundant Aβ deposits, mainly in the innermost retinal layers (RGCs and NFL) (40,42,45,49,52,54,57).…”

Section: Introductionmentioning

confidence: 80%

“…These studies, which included a variety of transgenic rat and mouse models, as well as the sporadic rodent model of AD, Octodon degus, demonstrated abundant Aβ deposits, mainly in the innermost retinal layers (RGCs and NFL) (40,42,45,49,52,54,57). Furthermore, several publications, including ours, have reported a positive response to therapy in reducing retinal Aβ plaque burden in transgenic (ADtg) murine models, often reflecting the reaction observed in the respective brains (40,48,51,52,56,60). To visualize retinal Aβ pathology in vivo, we had previously developed a noninvasive retinal amyloid imaging method for rodent ADtg models, using curcumin as a contrast agent (40,51).…”

Section: Introductionmentioning

confidence: 99%

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Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease

et al. 2017

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BACKGROUND. Noninvasive detection of Alzheimer's disease (AD) with high specificity and sensitivity can greatly facilitate identification of at-risk populations for earlier, more effective intervention. AD patients exhibit a myriad of retinal pathologies, including hallmark amyloid β-protein (Aβ) deposits. METHODS.Burden, distribution, cellular layer, and structure of retinal Aβ plaques were analyzed in flat mounts and cross sections of definite AD patients and controls (n = 37). In a proof-of-concept retinal imaging trial (n = 16), amyloid probe curcumin formulation was determined and protocol was established for retinal amyloid imaging in live patients. RESULTS.Histological examination uncovered classical and neuritic-like Aβ deposits with increased retinal Aβ 42 plaques (4.7-fold; P = 0.0063) and neuronal loss (P = 0.0023) in AD patients versus matched controls. Retinal Aβ plaque mirrored brain pathology, especially in the primary visual cortex (P = 0.0097 to P = 0.0018; Pearson's r = 0.84-0.91). Retinal deposits often associated with blood vessels and occurred in hot spot peripheral regions of the superior quadrant and innermost retinal layers. Transmission electron microscopy revealed retinal Aβ assembled into protofibrils and fibrils. Moreover, the ability to image retinal amyloid deposits with solid-lipid curcumin and a modified scanning laser ophthalmoscope was demonstrated in live patients. A fully automated calculation of the retinal amyloid index (RAI), a quantitative measure of increased curcumin fluorescence, was constructed. Analysis of RAI scores showed a 2.1-fold increase in AD patients versus controls (P = 0.0031). CONCLUSION.The geometric distribution and increased burden of retinal amyloid pathology in AD, together with the feasibility to noninvasively detect discrete retinal amyloid deposits in living patients, may lead to a practical approach for large-scale AD diagnosis and monitoring.

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Section: Introductionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease

et al. 2017

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“…Activated resident microglia released inflammatory factors and ROS, which caused the degeneration of ganglion cells and cholinergic amacrine cells in the retina of APPswe/PS1DE9 dtg mice. Furthermore, activated microglia promoted Müller cell proliferations and resulted in glial scar formation [92].…”

Section: Resident Microglia Mediate Aβ-induced Neurotoxicity In the Rmentioning

confidence: 99%

Friend or Foe? Resident Microglia vs Bone Marrow-Derived Microglia and Their Roles in the Retinal Degeneration

et al. 2016

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Microglia are immune cells in the central nervous system (CNS) that originate from the yolk sac in an embryo. The renewal of the microglia pool in the adult eye consists of two components. In addition to the self-proliferation of resident cells, microglia in the CNS also derive from the bone marrow (BM). BM-derived cells pass through the blood-brain barrier (BBB) or blood-retina barrier (BRB) and differentiate into microglia under specific conditions which involves a complex mechanism. Recent studies have widely investigated the role of resident microglia and BM-derived microglia in the retinal degenerative disease. Both two cell types play dual roles and share many similar functions. However, resident microglia tend to polarize to the M1 phenotype which is pro-inflammatory and neurotoxic, whereas BM-derived microglia mainly polarize to the neuroprotective M2 phenotype in retinal degeneration. The molecular mechanism that underlines the invasion of peripheral cells has led to extensive discussions. In addition to the BBB and BRB disruption, many signaling pathways are involved in this process. Based on these studies, we discuss the roles of these two types of microglia in retinal degeneration disease and the potential clinical application of BM-derived microglia, which may benefit future therapies.

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“…Immunofluorescence staining and terminal deoxynucleotidyl transferase UTP nick end labelling (TUNEL) assay of frozen tissue sections and cell slides were performed as previously described [33, 34]. Briefly, for frozen tissue sections, the eyeballs of the mice were enucleated and fixed in 4% paraformaldehyde at room temperature (RT) for 2 h. Meanwhile, the anterior segments were removed under a microscope (Olympus, Tokyo, Japan).…”

Section: Methodsmentioning

confidence: 99%

“…All positive cells from the TUNEL assay and iba1 staining in the whole sections were counted rather than selected locations in sections. Positive cells in each cell slide were counted in at least three different locations [33]. …”

Section: Methodsmentioning

confidence: 99%

Curcumin Delays Retinal Degeneration by Regulating Microglia Activation in the Retina of rd1 Mice

Wang

Yin

Gao

et al. 2017

Cell Physiol Biochem

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Background/Aims: Retinitis pigmentosa (RP) is characterized by degeneration of photoreceptors, and there are currently no effective treatments for this disease. However, curcumin has shown neuroprotectant efficacy in a RP rat and swine model, and thus, may have neuroprotective effects in this disease. Methods: Immunofluorescence staining, electroretinogram recordings, and behavioral tests were used to analyze the effects of curcumin and the underlying mechanism in retinal degeneration 1 (rd1) mice. Results: The number of apoptotic cells in the retina of rd1 mice at postnatal day 14 significantly decreased with curcumin treatment and visual function was improved. The activation of microglia and secretion of chemokines and matrix metalloproteinases in the retina were inhibited by curcumin. These effects were also observed in a co-culture of BV2 microglial cells and retina-derived 661W cells. Conclusions: Curcumin delayed retinal degeneration by suppressing microglia activation in the retina of rd1 mice. Thus, it may be an effective treatment for neurodegenerative disorders such as RP.

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Neuroprotective effect of memantine on the retinal ganglion cells of APPswe/PS1ΔE9 mice and its immunomodulatory mechanisms

Cited by 47 publications

References 52 publications

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease

Friend or Foe? Resident Microglia vs Bone Marrow-Derived Microglia and Their Roles in the Retinal Degeneration

Curcumin Delays Retinal Degeneration by Regulating Microglia Activation in the Retina of rd1 Mice

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