Potential therapeutic benefit of NAD+ supplementation for glaucoma and age-related macular degeneration

Glaucoma and age-related macular degeneration are leading causes of irreversible blindness worldwide with significant health and societal burdens. To date, no clinical cures are available and treatments target only the manageable symptoms and risk factors (but do not remediate the underlying pathology of the disease). Both diseases are neurodegenerative in their pathology of the retina and as such many of the events that trigger cell dysfunction, degeneration, and eventual loss are due to mitochondrial dysfunction, inflammation, and oxidative stress. Here, we critically review how a decreased bioavailability of nicotinamide adenine dinucleotide (NAD; a crucial metabolite in healthy and disease states) may underpin many of these aberrant mechanisms. We propose how exogenous sources of NAD may become a therapeutic standard for the treatment of these conditions. View Full-Text Keywords: nicotinamide adenine dinucleotide; glaucoma; age-related macular degeneration; mitochondria; retina; optic nerve; retinal pigment epitheliu

Ocular hypertension suppresses homeostatic gene expression in optic nerve head microglia of DBA/2 J mice.

Glaucoma is the leading cause of irreversible vision loss. Ocular hypertension is a major risk factor for glaucoma and recent work has demonstrated critical early neuroinflammatory insults occur in the optic nerve head following ocular hypertension. Microglia and infiltrating monocytes are likely candidates to drive these neuroinflammatory insults. However, the exact molecular identity / transcriptomic profile of microglia following ocular hypertensive insults is unknown. To elucidate the molecular identity of microglia after long-term exposure to ocular hypertension, we used a mouse model of glaucoma (DBA/2 J). We performed RNA-sequencing of microglia mRNA from the optic nerve head at a time point following ocular hypertensive insults, but preceding detectable neurodegeneration (with microglia identified as being CD4

Nicotinamide treatment robustly protects from inherited mouse glaucoma.

Nicotinamide adenine dinucleotide (NAD) is a key molecule in several cellular processes and is essential for healthy mitochondrial metabolism. We recently reported that mitochondrial dysfunction is among the very first changes to occur within retinal ganglion cells during initiation of glaucoma in DBA/2J mice. Furthermore, we demonstrated that an age-dependent decline of NAD contributes to mitochondrial dysfunction and vulnerability to glaucoma. The decrease in NAD renders retinal ganglion cells vulnerable to a metabolic crisis following periods of high intraocular pressure. Treating mice with the NAD precursor nicotinamide (the amide form of vitamin B3) inhibited many age- and high intraocular pressure- dependent changes with the highest tested dose decreasing the likelihood of developing glaucoma by ∼10-fold. In this communication, we present further evidence of the neuroprotective effects of nicotinamide against glaucoma in mice, including its prevention of optic nerve excavation and axon loss as assessed by histologic analysis and axon counting. We also show analyses of age- and intraocular pressure- dependent changes in transcripts of NAD producing enzymes within retinal ganglion cells and that nicotinamide treatment prevents these transcriptomic changes. Commun Integr Biol 2018; 11(1):e1356956

Glial metabolic alterations during glaucoma pathogenesis

Glaucoma is the leading cause of irreversible blindness. Current treatment options are limited and often only slow disease progression. Metabolic dysfunction has recently been recognized as a key early and persistent mechanism in glaucoma pathophysiology. Several intrinsic metabolic dysfunctions have been identified and treated in retinal ganglion cells to provide neuroprotection. Growing pre-clinical and clinical evidence has confirmed that metabolic alterations in glaucoma are widespread, occurring across visual system tissues, in ocular fluids, in blood/serum, and at the level of genomic and mitochondrial DNA. This suggests that metabolic dysfunction is not constrained to retinal ganglion cells and that metabolic alterations extrinsic to retinal ganglion cells may contribute to their metabolic compromise. Retinal ganglion cells are reliant on glial metabolic support under normal physiological conditions, but the implications of metabolic dysfunction in glia are underexplored. We highlight emerging evidence that has demonstrated metabolic alterations occurring within glia in glaucoma, and how this may affect neuro-glial metabolic coupling and the metabolic vulnerability of retinal ganglion cells. In other neurodegenerative diseases which share features with glaucoma, several other glial metabolic alterations have been identified, suggesting that similar mechanisms and therapeutic targets may exist in glaucoma

Modelling greenhouse gas emissions and mitigation potentials in fertilized paddy rice fields in Bangladesh

The work was supported by Bangabandhu Fellowship on Science and ICT project, Ministry of Science and Technology, People’s Republic of Bangladesh. We are grateful to the model developers at the Natural Resource Ecology Laboratory, Colorado State University, Fort Collins, Colorado, United States of America, for sending us the new methane version of the DayCent model.Peer reviewedPostprin

Digestion of the glycosaminoglycan extracellular matrix by chondroitinase ABC supports retinal ganglion cell dendritic preservation in a rodent model of experimental glaucoma

Retinal ganglion cell dendritic atrophy is an early feature of glaucoma, and the recovery of retinal ganglion cell dendrites is a viable option for vision improvement in glaucoma. Retinal ganglion cell neurites are surrounded by a specialised glycosaminoglycan extracellular matrix which inhibits dendritic plasticity. Since digestion of the extracellular matrix by chondroitinase ABC has been reported to have neuro-regenerative and neuro-plastic effects within the central nervous system, we explored its potential for dendritic recovery in a rat model of ocular hypertension. Chondroitinase ABC was administrated intravitreally 1 week after ocular hypertension (a time point where dendritic atrophy has already occurred). Retinal ganglion cell dendritic morphology was unaffected by chondroitinase ABC in normal retina. In ocular hypertensive eyes retinal ganglion cells showed significantly decreased dendritic length and area under the Sholl curve with atrophy confined to higher order dendrites. These changes were not observed in chondroitinase ABC injected eyes despite similar total retinal ganglion cell loss (i.e. dendritic protection of surviving retinal ganglion cells). These data suggest that glycosaminoglycan digestion could have a therapeutic role in mitigating the effects of elevated pressure on retinal ganglion cell dendritic structure in glaucoma

Complement peptide C3a receptor 1 promotes optic nerve degeneration in DBA/2J mice.

BACKGROUND: The risk of glaucoma increases significantly with age and exposure to elevated intraocular pressure, two factors linked with neuroinflammation. The complement cascade is a complex immune process with many bioactive end-products, including mediators of inflammation. Complement cascade activation has been shown in glaucoma patients and models of glaucoma. However, the function of complement-mediated inflammation in glaucoma is largely untested. Here, the complement peptide C3a receptor 1 was genetically disrupted in DBA/2J mice, an ocular hypertensive model of glaucoma, to test its contribution to neurodegeneration. METHODS: A null allele of C3ar1 was backcrossed into DBA/2J mice. Development of iris disease, ocular hypertension, optic nerve degeneration, retinal ganglion cell activity, loss of RGCs, and myeloid cell infiltration in C3ar1-deficient and sufficient DBA/2J mice were compared across multiple ages. RNA sequencing was performed on microglia from primary culture to determine global effects of C3ar1 on microglia gene expression. RESULTS: Deficiency in C3ar1 lowered the risk of degeneration in ocular hypertensive mice without affecting intraocular pressure elevation at 10.5 months of age. Differences were found in the percentage of mice affected, but not in individual characteristics of disease progression. The protective effect of C3ar1 deficiency was then overcome by additional aging and ocular hypertensive injury. Microglia and other myeloid-derived cells were the primary cells identified that express C3ar1. In the absence of C3ar1, microglial expression of genes associated with neuroinflammation and other immune functions were differentially expressed compared to WT. A network analysis of these data suggested that the IL10 signaling pathway is a major interaction partner of C3AR1 signaling in microglia. CONCLUSIONS: C3AR1 was identified as a damaging neuroinflammatory factor. These data help suggest complement activation causes glaucomatous neurodegeneration through multiple mechanisms, including inflammation. Microglia and infiltrating myeloid cells expressed high levels of C3ar1 and are the primary candidates to mediate its effects. C3AR1 appeared to be a major regulator of microglia reactivity and neuroinflammatory function due to its interaction with IL10 signaling and other immune related pathways. Targeting myeloid-derived cells and C3AR1 signaling with therapies is expected to add to or improve neuroprotective therapeutic strategies

OPA1 deficiency accelerates hippocampal synaptic remodelling and age-related deficits in learning and memory

A healthy mitochondrial network is essential for the maintenance of neuronal synaptic integrity. Mitochondrial and metabolic dysfunction contributes to the pathogenesis of many neurodegenerative diseases including dementia. OPA1 is the master regulator of mitochondrial fusion and fission and is likely to play an important role during neurodegenerative events. To explore this, we quantified hippocampal dendritic and synaptic integrity and the learning and memory performance of aged Opa1 haploinsufficient mice carrying the Opa1Q285X mutation (B6; C3-Opa1Q285STOP; Opa1+/−). We demonstrate that heterozygous loss of Opa1 results in premature age-related loss of spines in hippocampal pyramidal CA1 neurons and a reduction in synaptic density in the hippocampus. This loss is associated with subtle memory deficits in both spatial novelty and object recognition. We hypothesize that metabolic failure to maintain normal neuronal activity at the level of a single spine leads to premature age-related memory deficits. These results highlight the importance of mitochondrial homeostasis for maintenance of neuronal function during ageing

Inhibition of the classical pathway of the complement cascade prevents early dendritic and synaptic degeneration in glaucoma

BACKGROUND: Glaucoma is a complex, multifactorial disease characterised by the loss of retinal ganglion cells and their axons leading to a decrease in visual function. The earliest events that damage retinal ganglion cells in glaucoma are currently unknown. Retinal ganglion cell death appears to be compartmentalised, with soma, dendrite and axon changes potentially occurring through different mechanisms. There is mounting evidence from other neurodegenerative diseases suggesting that neuronal dendrites undergo a prolonged period of atrophy, including the pruning of synapses, prior to cell loss. In addition, recent evidence has shown the role of the complement cascade in synaptic pruning in glaucoma and other diseases. RESULTS: Using a genetic (DBA/2J mouse) and an inducible (rat microbead) model of glaucoma we first demonstrate that there is loss of retinal ganglion cell synapses and dendrites at time points that precede axon or soma loss. We next determine the role of complement component 1 (C1) in early synaptic loss and dendritic atrophy during glaucoma. Using a genetic knockout of C1qa (D2.C1qa (-/-) mouse) or pharmacological inhibition of C1 (in the rat bead model) we show that inhibition of C1 is sufficient to preserve dendritic and synaptic architecture. CONCLUSIONS: This study further supports assessing the potential for complement-modulating therapeutics for the prevention of retinal ganglion cell degeneration in glaucoma. Mol Neurodegener 2016 Apr 6; 11(2):2

Volume-rendered optical coherence tomography angiography during ocular interventions: Advocating for noninvasive intraoperative retinal perfusion monitoring.

We aimed to test for feasibility of volume-rendered optical coherence tomography angiography (OCTA) as a novel method for assessing/quantifying retinal vasculature during ocular procedures and to explore the potential for intraoperative use. Thirty patients undergoing periocular anaesthesia were enrolled, since published evidence suggests a reduction in ocular blood flow. Retinal perfusion was monitored based on planar OCTA image-derived data provided by a standard quantification algorithm and postprocessed/volume-rendered OCTA data using a custom software script. Overall, imaging procedures were successful, yet imaging artifacts occurred frequently. In interventional eyes, perfusion parameters decreased during anaesthesia. Planar image-derived and volume rendering-derived parameters were correlated. No correlation was found between perfusion parameters and a motion artifact score developed for this study, yet all perfusion parameters correlated with signal strength as displayed by the device. Concluding, volume-rendered OCTA allows for noninvasive three-dimensional retinal vasculature assessment/quantification in challenging surgical settings and appears generally feasible for intraoperative use