Distinct effects of inflammation on gliosis, osmohomeostasis, and vascular integrity during amyloid beta‐induced retinal degeneration

Abstract

SummaryIn normal retinas, amyloid-b (Ab) accumulates in the subretinal space, at the interface of the retinal pigment epithelium, and the photoreceptor outer segments. However, the molecular and cellular effects of subretinal Ab remain inadequately elucidated. We previously showed that subretinal injection of Ab(1-42) induces retinal inflammation, followed by photoreceptor cell death. The retinal Mü ller glial (RMG) cells, which are the principal retinal glial cells, are metabolically coupled to photoreceptors. Their role in the maintenance of retinal water ⁄ potassium and glutamate homeostasis makes them important players in photoreceptor survival. This study investigated the effects of subretinal Ab(1-42) on RMG cells and of Ab(1-42)-induced inflammation on retinal homeostasis. RMG cell gliosis (upregulation of GFAP, vimentin, and nestin) on day 1 postinjection and a proinflammatory phenotype were the first signs of retinal alteration induced by Ab(1-42). On day 3, we detected modifications in the protein expression patterns of cyclooxygenase 2 (COX-2), glutamine synthetase (GS), Kir4.1 [the inwardly rectifying potassium (Kir) channel], and aquaporin (AQP)-4 water channels in RMG cells and of the photoreceptor-associated AQP-1. The integrity of the blood-retina barrier was compromised and retinal edema developed. Ab(1-42) induced endoplasmic reticulum stress associated with sustained upregulation of the proapoptotic factors of the unfolded protein response and persistent photoreceptor apoptosis. Indomethacin treatment decreased inflammation and reversed the Ab(1-42)-induced gliosis and modifications in the expression patterns of COX-2, Kir4.1, and AQP-1, but not of AQP-4 or GS. Nor did it improve edema. Our study pinpoints the adaptive response to Ab of specific RMG cell functions.

MicroRNA Expression Patterns Involved in Amyloid Beta–Induced Retinal Degeneration

“…In the studies using C57BL/6, 15,37,39-42 the retina showed similar morphologic changes like disorganization of the photoreceptor nuclei and alteration of the inner segment (IS) and outer segment (OS) in the model group but these were still weaker than ours. Dinet et al 40 reported that very few apoptotic photoreceptors observed by day 3 became numerous in the retinas on day 7. In our study, neuron apoptosis appeared on day 2.…”

“…For the selection of the drug supply, most similar experiments adopted intravitreal 10,35,38 or subretinal 15,39,40 injection of Ab instead of intravenous injection. Intravitreal or subretinal injection can stimulate local pathogenesis to AMD more effectively than intravenous injection.…”

An evaluation of progressive amyloidogenic and pro-inflammatory change in the primary visual cortex and retina in Alzheimer's disease (AD)

“…Cycooxygenase-2 (COX-2; EC 1.14.99.1; 72 kDa) is the inducible, NF-kB-regulated isotype of the PTGSs, and as the rate-limiting enzyme of the arachidonic acid cycle is up-regulated in anatomical regions of AD brain where it potentiates inflammatory neuropathology (Lukiw and Bazan, 1998; Bazan and Lukiw, 2002; Hoozemans et al, 2008; Lukiw et al, 2012a,b; Cudaback et al, 2014). COX-2 expression, mean abundance, activity, and signaling is significantly up-regulated in both AD and age-related macular degeneration (AMD), a progressive degeneration of the human retina pathologically similar in many ways to the neocortical degeneration observed in AD neocortex (Hoozemans et al, 2008; Dinet et al, 2013; Rodríguez Diez et al, 2013). Notably, subretinal injection of Aβ 42 peptides using C57BL/6J mouse models was found to significantly induce COX-2 expression up to 6-fold while compromising the integrity of the blood-brain barrier and inducing retinal inflammation, photoreceptor cell death and driving a progressive retinal degeneration (Dinet et al, 2013).…”

“…COX-2 expression, mean abundance, activity, and signaling is significantly up-regulated in both AD and age-related macular degeneration (AMD), a progressive degeneration of the human retina pathologically similar in many ways to the neocortical degeneration observed in AD neocortex (Hoozemans et al, 2008; Dinet et al, 2013; Rodríguez Diez et al, 2013). Notably, subretinal injection of Aβ 42 peptides using C57BL/6J mouse models was found to significantly induce COX-2 expression up to 6-fold while compromising the integrity of the blood-brain barrier and inducing retinal inflammation, photoreceptor cell death and driving a progressive retinal degeneration (Dinet et al, 2013). While COX-2 remains a major player in the generation of oxygen radicals and lipid mediators in propagating inflammation in degenerating neocortex and retina, a third COX enzyme cyclooxygenase-3 (COX-3) may play ancillary roles in membrane-based COX signaling, however the role of COX-3 in AD and progressive neocortical and retinal disease is understudied and not well-understood (Cui et al, 2004; Wu and Wan, 2010).…”

Primary blast injury-induced lesions in the retina of adult rats

“…These molecules have been reported to be altered in the retina exposed to hypoxia [12] and smoke inhalation [13]. Furthermore, VEGF [14-16], AQP4 [17-19], NOS [20-22], nestin [19,23], GS [19], and glutamate [24], are known to be associated with vasodilation, tissue edema, and inflammatory reaction which have all been reported to be involved in retinal injury pathophysiology. We therefore sought to determine if these factors would be altered in the adult rat retina after blast exposure.…”