Glial and endothelial blood-retinal barrier responses to amyloid-&amp;beta; in the neural retina of the rat

Anderson, Peter J.; Watts, Helena; Hille, Christopher J.; Philpott, Karen L.; Clark, Peter; Gentleman, M Croucher S; Jen, L.S.

doi:10.2147/opth.s3967

Cited by 41 publications

(43 citation statements)

References 63 publications

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“…To evaluate the degree of glial activation, we used a scoring system based on the extent of GFAP staining [14] that has previously been used by our group [9,11,13].…”

Section: Animal Studiesmentioning

confidence: 99%

“…The Evans Blue albumin method was used as previously described with some modifications [14][15][16][17] (see ESM Methods). Digital images from different random fields of all retinas were acquired using a confocal laser scanning microscope (FV1000; Olympus) at ×20 using the 561 nm laser line, and each image was recorded with identical beam intensity at a size of 1024 pixels × 1024 pixels.…”

Section: Animal Studiesmentioning

confidence: 99%

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Topical administration of DPP-IV inhibitors prevents retinal neurodegeneration in experimental diabetes

et al. 2017

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Aims/hypothesis The main aims of the present study were: (1) to assess the expression and content of dipeptidyl peptidase IV (DPP-IV) in human and db/db mouse retinas, and in human vitreous fluid; and (2) to determine whether the topical administration of the DPP-IV inhibitors (DPP-IVi) would prevent retinal neurodegeneration and vascular leakage in db/db mice by reducing endogenous glucagon-like peptide 1 (GLP-1) degradation. Methods To assess the expression and content of DPP-IV, human samples of vitreous fluid and retinas were obtained from participants with type 2 diabetes (n = 8) and agematched non-diabetic individuals (n = 8), as well as from db/db (n = 72) and db/+ (n = 28) mice. The interventional study, which included 72 db/db mice, consisted of the topical administration (eye drops) of saxagliptin, sitagliptin or vehicle for 14 days. DPP-IV mRNA levels were assessed by RT-PCR, and protein content was measured by ELISA or western blotting. GLP-1 was assessed by immunofluorescence, and its downstream effector exchange protein activated by cAMP-1 (EPAC-1) was used as a measure of GLP-1 receptor activation. Retinal analyses were performed in vivo by electroretinography and ex vivo by RT-PCR (Epac-1, Iba-1 [also known as Aif1]), western blotting (EPAC-1, glial fibrillar acidic protein [GFAP], glutamate−aspartate transporter [GLAST]) and immunofluorescence measurements (GLP-1, GFAP, ionised calcium binding adaptor molecule 1 [IBA-1], TUNEL, GLAST, albumin and collagen IV). Glutamate was quantified by HPLC. In addition, vascular leakage was examined by the Evans Blue method. Results DPP-IV was present in human vitreous fluid but in a range 100-fold less than in plasma. Both mRNA levels and protein content were much lower in the retina than in the liver or bowel, but were significantly higher in retinal pigment epithelium (RPE) from diabetic donors in comparison to non-diabetic donors (p < 0.05). Topical treatment with DPP-IVi prevented glial activation, apoptosis and vascular leakage induced by diabetes in db/db mice (p < 0.05). Moreover, it also significantly prevented diabetes-induced functional abnormalities in the electroretinogram. A significant increase of both GLP-1 and EPAC-1 was found after treatment with DPP-IVi (p < 0.05). Furthermore, GLAST downregulation induced by diabetes was prevented, resulting in a significant reduction of extracellular glutamate concentrations. All these effects were observed without any changes in blood glucose levels. Conclusions/interpretation The topical administration of DPP-IVi is effective in preventing neurodegeneration and vascular leakage in the diabetic retina. These effects can be attributed to an enhancement of GLP-1, but other mechanisms unrelated to the prevention of GLP-1 degradation cannot be ruled out.

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“…To evaluate the degree of glial activation, we used a scoring system based on the extent of GFAP staining [14] that has previously been used by our group [9,11,13].…”

Section: Animal Studiesmentioning

confidence: 99%

Section: Animal Studiesmentioning

confidence: 99%

Topical administration of DPP-IV inhibitors prevents retinal neurodegeneration in experimental diabetes

et al. 2017

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“…26 To evaluate the degree of glial activation, we used a scoring system based on extent of GFAP staining 28 which had previously been used by our group. 25,26 Briefly, the scoring system used was as follows: Muller cell endfeet region/GCL only (score 1); Muller cell endfeet region/GCL plus a few proximal processes (score 2); Muller cell endfeet plus many processes, but not extending to the outer nuclear layer (ONL (score 3); Muller cell endfeet plus processes throughout with some in the ONL (score 4); and Muller cell endfeet plus many dark processes from GCL extending to the outer margin of the ONL (score 5).…”

Section: Glial Activationmentioning

confidence: 99%

Calcium Dobesilate Prevents Neurodegeneration and Vascular Leakage in Experimental Diabetes

Solà-Adell

Bogdanov

Hernández

et al. 2017

Current Eye Research

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Purpose: The mechanisms involved in the reported beneficial effects of Calcium dobesilate monohydrate (CaD) for the treatment of diabetic retinopathy (DR) remain to be elucidated. The main aim of the present study is to examine whether CaD prevents early events in the pathogenesis of DR such as neurodegeneration and vascular leakage. In addition, putative mediators of both neurodegeneration (glutamate/GLAST, ET-1/ETB receptor) and early microvascular impairment (ET-1/ETA receptor, oxidative stress, VEGF, and the PKC-delta-p38 MAPK pathway) have been examined. Methods: Diabetic (db/db) mice were randomly assigned to daily oral treatment with CaD (200 mg/Kg/ day) (n = 12) or vehicle (n = 12) for 14 days. In addition, 12 non-diabetic (db/+) mice matched by age were used as the control group. Functional abnormalities were assessed by electroretinography. Neurodegeneration and microvascular abnormalities were evaluated by immunohistochemistry and Western blot. Glutamate was determined by HPLC. Results: CaD significantly decreased glial activation and apoptosis and produced a significant improvement in the electroretinogram parameters. Mechanistically, CaD prevented the diabetes-induced upregulation of ET-1 and its cognate receptors (ETA-R and ETB-R), which are involved in microvascular impairment and neurodegeneration, respectively. In addition, treatment with CaD downregulated GLAST, the main glutamate transporter, and accordingly prevented the increase in glutamate. Finally, CaD prevented oxidative stress, and the upregulation of VEGF and PKC delta-p38 MAPK pathway induced by diabetes, thus resulting in a significant reduction in vascular leakage.Conclusions: Our findings demonstrate for the first time that CaD exerts neuroprotection in an experimental model of DR. In addition, we provide first evidence that CaD prevents the overexpression of ET-1 and its receptors in the diabetic retina. These beneficial effects on the neurovascular unit could pave the way for clinical trials addressed to confirm the effectiveness of CaD in very early stages of DR. ARTICLE HISTORY

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“…Our investigations to date have suggested that a single intravitreal injection of preaggregated Aβ can precipitate degenerative changes in multiple interacting cellular systems including neuronal apoptosis, severe glial activation, immune reactivity, and blood retinal barrier breakdown. 6,[22][23][24] The aim of the present study was to clarify the relationship between Aβ aggregation state and neurotoxicity in vivo. To this end, we have compared Aβ 1-42 prepared under conditions that favor either (1) sAβ (monomers and small oligomers), or solutions that have been (2) preincubated for several days to increase fibril formation, or (3) preincubated for an extended period to obtain highly fibrillar Aβ species.…”

mentioning

confidence: 99%

“…A full description of the retinal glial responses to Aβ 1-42 injection observed in these experiments is reported separately. 24 retinal atrophy at 1-month survival…”

mentioning

confidence: 99%

Differential effects of amyloid-beta peptide aggregation status on in vivo retinal neurotoxicity

Watts

Anderson

et al. 2010

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Abstract:The present study examined the relationship between amyloid beta (Aβ)-peptide aggregation state and neurotoxicity in vivo using the rat retinal-vitreal model. Following single unilateral intravitreal injection of either soluble Aβ 1-42 or Aβ 1-42 preaggregated for different periods, retinal pathology was evaluated at 24 hours, 48 hours, and 1-month postinjection. Injection of either soluble Aβ (sAβ) or preaggregated Aβ induced a rapid reduction in immunoreactivity (IR) for synaptophysin, suggesting that direct contact with neurons is not necessary to disrupt synapses. Acute neuronal ionic and metabolic dysfunction was demonstrated by widespread loss of IR to the calcium buffering protein parvalbumin (PV) and protein gene product 9.5, a component of the ubiquitin-proteosome system. Injection of sAβ appeared to have a more rapid impact on PV than the preaggregated treatments, producing a marked reduction in PV cell diameters at 48 hours, an effect that was only observed for preaggregated Aβ after 1-month survival. Extending the preaggregation period from 4 to 8 days to obtain highly fibrillar Aβ species significantly increased the loss of choline acteyltransferase IR, but had no effect on PV-IR. These findings prompt the conclusion that Aβ assembly state has a significant impact on in vivo neurotoxicity by triggering distinct molecular changes within the cell.

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Glial and endothelial blood-retinal barrier responses to amyloid-β in the neural retina of the rat

Cited by 41 publications

References 63 publications

Topical administration of DPP-IV inhibitors prevents retinal neurodegeneration in experimental diabetes

Topical administration of DPP-IV inhibitors prevents retinal neurodegeneration in experimental diabetes

Calcium Dobesilate Prevents Neurodegeneration and Vascular Leakage in Experimental Diabetes

Differential effects of amyloid-beta peptide aggregation status on in vivo retinal neurotoxicity

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