Toll-like receptor 3 and geographic atrophy in age-related macular degeneration.

BACKGROUND: Age-related macular degeneration is the most common cause of irreversible visual impairment in the developed world. Advanced age-related macular degeneration consists of geographic atrophy and choroidal neovascularization. The specific genetic variants that predispose patients to geographic atrophy are largely unknown. METHODS: We tested for an association between the functional toll-like receptor 3 gene (TLR3) variant rs3775291 (involving the substitution of phenylalanine for leucine at amino acid 412) and age-related macular degeneration in Americans of European descent. We also tested for the effect of TLR3 Leu and Phe variants on the viability of human retinal pigment epithelial cells in vitro and on apoptosis of retinal pigment epithelial cells from wild-type mice and Tlr3-knockout (Tlr3(-/-)) mice. RESULTS: The Phe variant (encoded by the T allele at rs3775291) was associated with protection against geographic atrophy (P=0.005). This association was replicated in two independent case-control series of geographic atrophy (P=5.43x10(-4) and P=0.002). No association was found between TLR3 variants and choroidal neovascularization. A prototypic TLR3 ligand induced apoptosis in a greater fraction of human retinal pigment epithelial cells with the Leu-Leu genotype than those with the Leu-Phe genotype and in a greater fraction of wild-type mice than Tlr3(-/-) mice. CONCLUSIONS: The TLR3 412Phe variant confers protection against geographic atrophy, probably by suppressing the death of retinal pigment epithelial cells. Since double-stranded RNA (dsRNA) can activate TLR3-mediated apoptosis, our results suggest a role of viral dsRNA in the development of geographic atrophy and point to the potential toxic effects of short-interfering-RNA therapies in the eye.

Selective death of newborn neurons in hippocampal dentate gyrus following moderate experimental traumatic brain injury.

Memory impairment is one of the most significant residual deficits following traumatic brain injury (TBI) and is among the most frequent complaints heard from patients and their relatives. It has been reported that the hippocampus is particularly vulnerable to TBI, which results in hippocampus-dependent cognitive impairment. There are different regions in the hippocampus, and each region is composed of different cell types, which might respond differently to TBI. However, regional and cell type-specific neuronal death following TBI is not well described. Here, we examined the distribution of degenerating neurons in the hippocampus of the mouse brain following controlled cortical impact (CCI) and found that the majority of degenerating neurons observed were in the dentate gyrus after moderate (0.5 mm cortical deformation) CCI-TBI. In contrast, there were only a few degenerating neurons observed in the hilus, and we did not observe any degenerating neurons in the CA3 or CA1 regions. Among those degenerating cells in the dentate gyrus, about 80% of them were found in the inner granular neuron layer. Analysis with cell type-specific markers showed that most of the degenerating neurons in the inner granular neuron layer are newborn immature neurons. Further quantitative analysis shows that the number of newborn immature neurons in the dentate gyrus is dramatically decreased in the ipsilateral hemisphere compared with the contralateral side. Collectively, our data demonstrate the selective death of newborn immature neurons in the hippocampal dentate gyrus following moderate injury with CCI in mice. This selective vulnerability of newborn immature dentate neurons may contribute to the persistent impairment of learning and memory post-TBI and provide an innovative target for neuroprotective treatment strategies.

Evolution of post-traumatic neurodegeneration after controlled cortical impact traumatic brain injury in mice and rats as assessed by the de Olmos silver and fluorojade staining methods.

This report documents an analysis of post-traumatic neurodegeneration during the first 7 days after controlled cortical impact (CCI) traumatic brain injury (TBI) in mice and rats using the de Olmos aminocupric silver staining method, which selectively stains degenerating axons and nerve terminals, compared to the fluorojade method, which stains degenerating neuronal cell bodies. A progressive increase in cortical, hippocampal, and thalamic degeneration was observed over the first 48 h after injury in both species. Approximately 50% of the ipsilateral cortical volume was stained at 48 h. Similarly, the dorsal hippocampus showed widespread degeneration in all of the subfields. This included CA1, CA3, CA4, and dentate cell bodies revealed by fluorojade together with a high degree of axonal degeneration in areas carrying afferent and efferent hippocampal projections that is identified by silver staining. These results show that previous CCI studies which have relied on conventional histological methods that show cell body staining alone have underestimated the degree of axonal damage associated with the CCI-TBI model. In order to capture the full extent of the injury to both axons and cell bodies, the combination of silver staining and fluorojade staining is needed, respectively. Future studies of potential neuroprotective agents should probably not rely on the measure of cortical lesion volume or volume of spared cortical tissue using conventional histological stains alone, since these fail to identify the complete extent of the posttraumatic neuropathology that some agents which reduce cortical lesion volume may not be able to effect.

Beneficial effects of rosmarinic acid on suppression of collagen induced arthritis.

OBJECTIVE: To assess the therapeutic potential of rosmarinic acid (RosA) in an inflammatory autoimmune arthritis model. METHODS: Collagen induced arthritis is established in male DBA/1 mice. Mice were administered daily with 50 mg/kg/day of RosA for 15 days from Day 21 post-immunization and inspected daily to determine the progression of arthritis. After termination of injection, affected hindpaws were subjected to histopathological analyses and immunohistochemical assays for cyclooxygenase-2 (COX-2) expression. RESULTS: Repeated administration of RosA dramatically reduced the arthritic index and number of affected paws. Histopathologic observations closely paralleled clinical data, showing that RosA treated mice retained nearly normal architecture of synovial tissues, whereas control mice exhibited severe synovitis. Synovial tissues from RosA treated mice exhibited remarkably reduced frequency of COX-2-expressing cells, compared to those from untreated mice. CONCLUSION: RosA suppressed synovitis in a murine collagen induced arthritis model; this effect may be beneficial for treatment of rheumatoid arthritis in clinical settings.