Assessment of Lab4P Probiotic Effects on Cognition in 3xTg-AD Alzheimer's Disease Model Mice and the SH-SY5Y Neuronal Cell Line.

Aging and metabolic syndrome are associated with neurodegenerative pathologies including Alzheimer's disease (AD) and there is growing interest in the prophylactic potential of probiotic bacteria in this area. In this study, we assessed the neuroprotective potential of the Lab4P probiotic consortium in both age and metabolically challenged 3xTg-AD mice and in human SH-SY5Y cell culture models of neurodegeneration. In mice, supplementation prevented disease-associated deteriorations in novel object recognition, hippocampal neurone spine density (particularly thin spines) and mRNA expression in hippocampal tissue implying an anti-inflammatory impact of the probiotic, more notably in the metabolically challenged setting. In differentiated human SH-SY5Y neurones challenged with ß-Amyloid, probiotic metabolites elicited a neuroprotective capability. Taken together, the results highlight Lab4P as a potential neuroprotective agent and provide compelling support for additional studies in animal models of other neurodegenerative conditions and human studies.

Retinal Ganglion Cell Degeneration in a Rat Magnetic Bead Model of Ocular Hypertensive Glaucoma.

Purpose: Glaucoma remains a leading cause of irreversible blindness worldwide. Animal glaucoma models replicate high intraocular pressure, a risk factor for glaucoma, to induce retinal ganglion cell (RGC) degeneration. We describe an inducible, magnetic bead model in the Brown Norway rat in which we are able to determine degeneration across multiple RGC compartments at a time point that is appropriate for investigating neurodegenerative events and potential treatment effects. Methods: We induced ocular hypertension through injection of magnetic microspheres into the anterior chamber of Brown Norway rats; un-operated (naïve) rats served as controls. Intraocular pressure was recorded, and eye diameter measurements were taken before surgery and at the terminal end points. We assessed RGC degeneration and vascular changes through immunofluorescence, and axon transport to terminal brain thalami through intravitreal injection of fluorophore-conjugated cholera toxin subunit ß. Results: We observed clinically relevant features of disease accompanying RGC cell somal, axonal, and dendritic loss. RGC axonal dysfunction persisted along the trajectory of the cell into the terminal brain thalami, with clear disruption at the optic nerve head. We also observed vascular compromise consistent with human disease, as well as an expansion of global eye size with ocular hypertension. Conclusions: The magnetic bead model in the Brown Norway rat recapitulates many clinically relevant disease features of human glaucoma, including degeneration across multiple RGC compartments. Eye expansion is likely a result of rodent scleral elasticity, and we caution that this should be considered when assessing retinal density measurements. Translational Relevance: This model offers a disease-relevant platform that will allow for assessment of glaucoma-relevant therapeutics.

Associations with Intraocular Pressure in a Large Cohort: Results from the UK Biobank.

PURPOSE: To describe the associations of physical and demographic factors with Goldmann-correlated intraocular pressure (IOPg) and corneal-compensated intraocular pressure (IOPcc) in a British cohort. DESIGN: Cross-sectional study within the UK Biobank, a large-scale multisite cohort study in the United Kingdom. PARTICIPANTS: We included 110 573 participants from the UK Biobank with intraocular pressure (IOP) measurements available. Their mean age was 57 years (range, 40-69 years); 54% were women, and 90% were white. METHODS: Participants had 1 IOP measurement made on each eye using the Ocular Response Analyzer noncontact tonometer. Linear regression models were used to assess the associations of IOP with physical and demographic factors. MAIN OUTCOME MEASURES: The IOPg and IOPcc. RESULTS: The mean IOPg was 15.72 mmHg (95% confidence interval [CI], 15.70-15.74 mmHg), and the mean IOPcc was 15.95 mmHg (15.92-15.97 mmHg). After adjusting for covariates, IOPg and IOPcc were both significantly associated with older age, male sex, higher systolic blood pressure (SBP), faster heart rate, greater myopia, self-reported glaucoma, and colder season (all P < 0.001). The strongest determinants of both IOPg and IOPcc were SBP (partial R(2): IOPg 2.30%, IOPcc 2.26%), followed by refractive error (IOPg 0.60%, IOPcc 1.04%). The following variables had different directions of association with IOPg and IOPcc: height (-0.77 mmHg/m IOPg; 1.03 mmHg/m IOPcc), smoking (0.19 mmHg IOPg, -0.35 mmHg IOPcc), self-reported diabetes (0.41 mmHg IOPg, -0.05 mmHg IOPcc), and black ethnicity (-0.80 mmHg IOPg, 0.77 mmHg IOPcc). This suggests that height, smoking, diabetes, and ethnicity are related to corneal biomechanical properties. The increase in both IOPg and IOPcc with age was greatest among those of mixed ethnicities, followed by blacks and whites. The same set of covariates explained 7.4% of the variability of IOPcc but only 5.3% of the variability of IOPg. CONCLUSIONS: This analysis of associations with IOP in a large cohort demonstrated that some variables clearly have different associations with IOPg and IOPcc, and that these 2 measurements may reflect different biological characteristics.

VEGF-A is necessary and sufficient for retinal neuroprotection in models of experimental glaucoma.

Vascular endothelial growth factor A (VEGF-A) is a validated therapeutic target in several angiogenic- and vascular permeability-related pathological conditions, including certain cancers and potentially blinding diseases, such as age-related macular degeneration and diabetic retinopathy. We and others have shown that VEGF-A also plays an important role in neuronal development and neuroprotection, including in the neural retina. Antagonism of VEGF-A function might therefore present a risk to neuronal survival as a significant adverse effect. Herein, we demonstrate that VEGF-A acts directly on retinal ganglion cells (RGCs) to promote survival. VEGF receptor-2 signaling via the phosphoinositide-3-kinase/Akt pathway was required for the survival response in isolated RGCs. These results were confirmed in animal models of staurosporine-induced RGC death and experimental hypertensive glaucoma. Importantly, we observed that VEGF-A blockade significantly exacerbated neuronal cell death in the hypertensive glaucoma model. Our findings highlight the need to better define the risks associated with use of VEGF-A antagonists in the ocular setting.

Cellular inhibitor of apoptosis (cIAP1) is down-regulated during retinal ganglion cell (RGC) maturation.

Apoptosis, is the main type of cell death that occurs in ageing and neurodegenerative disease, such as glaucoma. This study therefore characterises the expression profile of caspases (pro-apoptosis) and inhibitors of apoptosis (IAPs; anti-apoptosis) during maturation of the Brown Norway rat retina between 6 weeks and >24 weeks and also examines concomitant changes in expression of tumor necrosis factor receptor associated factor 2 (TRAF2). The expression profiles of caspases (initiator caspases 8, 9 and effector caspases 6, 7, 3) and inhibitors of apoptosis (IAPs) (Neuronal IAP), cellular IAP1 and 2 (cIAP1/2), X-chromosome linked IAP (XIAP), Survivin, Bruce and Livin) were examined in retinae from 6 weeks and >24 weeks old BN rats using semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), real-time PCR, Western blotting and immunofluoroscence analysis. Caspase expression was not altered significantly during the study interval. IAP expression showed a general reduction during maturation of BN retina, which was statistically significant for cIAP1. cIAP1 reduction was confirmed by Western blotting and immunoflouroscence and was restricted to cells in the retinal ganglion cell layer (RGCL). Accumulation of TRAF2 was observed in the RGCL accompanying the down-regulation of cIAP1 observed. Our results suggest that cells in the mature RGCL may have a greater susceptibility to cell death compared to their younger counterparts and this may be due in part to a reduction in activation of survival pathways involving IAPs and TRAFs.

Transscleral cyclodiode laser photocoagulation in the treatment of aqueous misdirection syndrome.

PURPOSE: To describe the outcome of using transscleral cyclodiode laser ciliary body ablation as a novel treatment for aqueous misdirection syndrome. DESIGN: Retrospective case series review. PARTICIPANTS: Five patients diagnosed with aqueous misdirection syndrome. INTERVENTION: Patients successfully managed using transscleral cyclodiode laser. MAIN OUTCOME MEASURES: To evaluate demographic information, risk factors, visual acuity, medical treatment, intraocular pressure (IOP) control, and complications. RESULTS: The patients were aged 27 to 78 years and 3 were female. All were hyperopic, with narrow iridocorneal angles and patent peripheral iridotomies (PI). Four developed aqueous misdirection syndrome after intraocular surgery and 1 developed it spontaneously in the presence of a patent PI after losing vision in the fellow eye to the same condition 8 years earlier. All 5 patients responded to transscleral cyclodiode laser photocoagulation with rapid deepening of the anterior chamber; 1 patient required a second treatment 1 year later. All patients had good long-term vision and IOP control. CONCLUSIONS: The outcome of transscleral cyclodiode ciliary body ablation in these patients supports the use of this technique in cases of aqueous misdirection syndrome where medical treatment has not been sufficient to control the IOP.