Early Stages Of Degeneration Research Articles

Nigrostriatal degeneration determines dynamics of glial inflammatory and phagocytic activity

Glial cells are key players in the initiation of innate immunity in neurodegeneration. Upon damage, they switch their basal activation state and acquire new functions in a context and time-dependent manner. Since modulation of neuroinflammation is becoming an interesting approach for the treatment of neurodegenerative diseases, it is crucial to understand the specific contribution of these cells to the inflammatory reaction and to select experimental models that recapitulate what occurs in the human disease. Previously, we have characterized a region-specific activation pattern of CD11b+ cells and astrocytes in the α-synuclein overexpression mouse model of Parkinson´s disease (PD). In this study we hypothesized that the time and the intensity of dopaminergic neuronal death would promote different glial activation states. Dopaminergic degeneration was induced with two administration regimens of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), subacute (sMPTP) and chronic (cMPTP). Our results show that in the sMPTP mouse model, the pro-inflammatory phenotype of striatal CD11b+ cells was counteracted by an anti-inflammatory astrocytic profile. In the midbrain the roles were inverted, CD11b+ cells exhibited an anti-inflammatory profile and astrocytes were pro-inflammatory. The overall response generated resulted in decreased CD4 T cell infiltration in both regions. Chronic MPTP exposure resulted in a mild and prolonged neuronal degeneration that generated a pro-inflammatory response and increased CD4 T cell infiltration in both regions. At the onset of the neurodegenerative process, microglia and astrocytes cooperated in the removal of dopaminergic terminals. With time, only microglia maintained the phagocytic activity. In the ventral midbrain, astrocytes were the main phagocytic mediators at early stages of degeneration while microglia were the major phagocytic cells in the chronic state. In this scenario, we questioned which activation pattern recapitulates better the features of glial activation in PD. Glial activation in the cMPTP mouse model reflects many pathways of their corresponding counterparts in the human brain with advanced PD. Altogether, our results point toward a context-dependent cooperativity of microglia/myeloid cells and astrocytes in response to neuronal damage and the relevance of selecting the right experimental models for the study of neuroinflammation.Graphical abstract

Selective Block of Upregulated Kv1.3 Potassium Channels in ON-Bipolar Cells of the Blind Retina Enhances Optogenetically Restored Signaling.

Loss of photoreceptors in retinal degenerative diseases also impacts the inner retina: bipolar cell dendrites retract, neurons rewire, and protein expression changes. ON-bipolar cells (OBCs) represent an attractive target for optogenetic vision restoration. However, the above-described maladaptations may negatively impact the quality of restored vision. To investigate this question, we employed human post-mortem retinas and transgenic rd1_Opto-mGluR6 mice expressing the optogenetic construct Opto-mGluR6 in OBCs and carrying the retinal degeneration rd1 mutation. We found significant changes in delayed rectifier potassium channel expression in OBCs of degenerative retinas. In particular, we found an increase in Kv1.3 expression already in early stages of degeneration. Immunohistochemistry localized Kv1.3 channels specifically to OBC axons. In whole-cell patch-clamp experiments, OBCs in the degenerated murine retina were less responsive, which could be reversed by application of the specific Kv1.3 antagonist Psora-4. Notably, Kv1.3 block significantly increased the amplitude and kinetics of Opto-mGluR6-mediated light responses in OBCs of the blind retina and increased the signal-to-noise ratio of light-triggered responses in retinal ganglion cells. We propose that reduction in Kv1.3 activity in the degenerated retina, either by pharmacological block or by KCNA3 gene silencing, could improve the quality of restored vision.

Cell clusters in intervertebral disc degeneration: an attempted repair mechanism aborted via apoptosis.

Cell clusters are a histological hallmark feature of intervertebral disc degeneration. Clusters arise from cell proliferation, are associated with replicative senescence, and remain metabolically, but their precise role in various stages of disc degeneration remain obscure. The aim of this study was therefore to investigate small, medium, and large size cell-clusters. For this purpose, human disc samples were collected from 55 subjects, aged 37-72 years, 21 patients had disc herniation, 10 had degenerated non-herniated discs, and 9 had degenerative scoliosis with spinal curvature <45°. 15 non-degenerated control discs were from cadavers. Clusters and matrix changes were investigated with histology, immunohistochemistry, and Sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE). Data obtained were analyzed with spearman rank correlation and ANOVA. Results revealed, small and medium-sized clusters were positive for cell proliferation markers Ki-67 and proliferating cell nuclear antigen (PCNA) in control and slightly degenerated human discs, while large cell clusters were typically more abundant in severely degenerated and herniated discs. Large clusters associated with matrix fissures, proteoglycan loss, matrix metalloproteinase-1 (MMP-1), and Caspase-3. Spatial association findings were reconfirmed with SDS-PAGE that showed presence to these target markers based on its molecular weight. Controls, slightly degenerated discs showed smaller clusters, less proteoglycan loss, MMP-1, and Caspase-3. In conclusion, cell clusters in the early stages of degeneration could be indicative of repair, however sustained loading increases large cell clusters especially around microscopic fissures that accelerates inflammatory catabolism and alters cellular metabolism, thus attempted repair process initiated by cell clusters fails and is aborted at least in part via apoptosis.

Gene Therapies for Retinitis Pigmentosa that Target Glucose Metabolism.

Retinitis pigmentosa is a blinding disease wherein rod photoreceptors are affected first, due to the expression of a disease gene, leading to the loss of dim light vision. In many cases, cones do not express the disease gene, yet they are also affected and eventually die, typically after most of the rods in their neighborhood have died. The cause of secondary cone death is unclear. Photoreceptors are one of the most energy-demanding cell types in the body and consume a high amount of glucose. At an early stage of degeneration, the cones appear to have a shortage of glucose to fuel their metabolism. This review focuses on gene therapy approaches that address this potential metabolic shortcoming.

DOES BONE TURNOVER EXPLAIN HIGH BONE DENSITY IN FEMOROACETABULAR IMPINGEMENT? AN ANALYSIS OF PET AND CT IMAGING

Femoroacetabular impingement (FAI) results from a morphological deformity of the hip and is associated with osteoarthritis (OA). Increased bone mineral density (BMD) is observed in the antero-superior acetabulum rim where impingement occurs. It is hypothesized that the repeated abnormal contact leads to damage of the cartilage layer, but could also cause a bone remodelling response according to Wolff's Law. Thus the goal of this study was to assess the relationship between bone metabolic activity measured by PET and BMD measured in CT scans.Five participants with asymptomatic cam deformity, three patients with uni-lateral symptomatic cam FAI and three healthy controls were scanned in a 3T PET-MRI scanner following injection with [18F]NaF. Bone remodelling activity was quantified with Standard Uptake Values (SUVs). SUVmax was analyzed in the antero-superior acetabular rim, femoral head and head-neck junction. In these same regions, BMD was calculated from CT scans using the calibration phantom included in the scan. The relationship between SUVmax and BMD from corresponding regions was assessed using the coefficient of determination (R2) from linear regression.High bone activity was seen in the cam deformity and acetabular rim. SUVmax was negatively correlated with BMD in the antero-superior region of the acetabulum (R2=0.30, p=0.08). SUVmax was positively correlated with BMD in the antero-superior head-neck junction of the femur (R2=0.359, p=0.067). Correlations were weak in other regions.Elevated bone turnover was seen in patients with a cam deformity but the relationship to BMD was moderate. This study demonstrates a pathomechanism of hip degeneration associated with FAI deformities, consistent with Wolff's law and the proposed mechanical cause of hip degeneration in FAI. [18F]-NaF PET SUV may be a biomarker of degeneration, especially in early stages of degeneration, when joint preservation surgery is likely to be the most successful.

Photobiology of lipofuscin granules in the retinal pigment epithelium cells of the eye: norm, pathology, age.

Lipofuscin granules (LGs) are accumulated in the retinal pigment epithelium (RPE) cells. The progressive LG accumulation can somehow lead to pathology and accelerate the aging process. The review examines composition, spectral properties and photoactivity of LGs isolated from the human cadaver eyes. By use of atomic force microscopy and near-field microscopy, we have revealed the fluorescent heterogeneity of LGs. We have discovered the generation of reactive oxygen species by LGs, and found that LGs and melanolipofuscin granules are capable of photoinduced oxidation of lipids. It was shown that A2E, as the main fluorophore (bisretinoid) of LGs, is much less active as an oxidation photosensitizer than other fluorophores (bisretinoids) of LGs. Photooxidized products of bisretinoids pose a much greater danger to the cell than non-oxidized one. Our studies of the fluorescent properties of LGs and their fluorophores (bisretinoids) showed for the first time that their spectral characteristics change (shift to the short-wavelength region) in pathology and after exposure to ionizing radiation. By recording the fluorescence spectra and fluorescence decay kinetics of oxidized products of LG fluorophores, it is possible to improve the methods of early diagnosis of degenerative diseases. Lipofuscin ("aging pigment") is not an inert "slag". The photoactivity of LGs can pose a significant danger to the RPE cells. Fluorescence characteristics of LGs are a tool to detect early stages of degeneration in the retina and RPE.

Cervical spine degeneration specific segmental angular rotational and displacements: A quantitative study

BackgroundThe objective of the present isolated spine study was to evaluate the kinematic differences between groups of normal and degenerated cervical spine specimens. Previous studies on cervical spine degeneration support the existence of the unstable phase during the degeneration process; however, there is a lack of quantitative data available to fully characterize this early stage of degeneration. MethodFor this effort five degenerated and eight normal cervical spines (C2-T1) were isolated and were subject to pure bending moments of flexion, extension, axial rotation and lateral bending. The specimen quality was assessed based on the grading scale. In the present study, the degeneration was at the C5-C6 level. A four-camera motion analysis system was used to measure the overall primary and segmental motions. FindingIn the extension mode, the degenerated group demonstrated a significant larger angular rotation as well as antero-posterior displacement at the degenerated level (C5-C6). In contrast, in flexion mode, the degenerated group measured a drastic decrease in angular rotation, at the adjacent level (C6-C7). In other modes of loading as well as in other segmental levels, the degenerated group had similar segmental motion as the normal group. InterpretationThese preliminary results provide single level degeneration specific cervical spine kinematics. The finding demonstrates the influence of degeneration on the kinematics of the normal sub adjacent segment. The degenerated group observed larger translation displacement in the extension mode, which would potentially be a critical parameter in assisting early detection of cervical spine spondylosis with just a functional X-ray scan.

Bioengineering strategies for restoring vision.

Late-stage retinal degenerative disease involving photoreceptor loss can be treated by optogenetic therapy, cell transplantation and retinal prostheses. These approaches aim to restore light sensitivity to the retina as well as visual perception by integrating neuronal responses for transmission to the cortex. In age-related macular degeneration, some cell-based therapies also aim to restore photoreceptor-supporting tissue to prevent complete photoreceptor loss. In the earlier stages of degeneration, gene-replacement therapy could attenuate retinal-disease progression and reverse loss of function. And gene-editing strategies aim to correct the underlying genetic defects. In this Review, we highlight the most promising gene therapies, cell therapies and retinal prostheses for the treatment of retinal disease, discuss the benefits and drawbacks of each treatment strategy and the factors influencing whether functional tissue is reconstructed and repaired or replaced with an electronic device, and summarize upcoming technologies for enhancing the restoration of vision.

Super-resolution microscopy reveals photoreceptor-specific subciliary location and function of ciliopathy-associated protein CEP290.

Mutations in the cilium-associated protein CEP290 cause retinal degeneration as part of multiorgan ciliopathies or as retina-specific diseases. The precise location and the functional roles of CEP290 within cilia and, specifically, the connecting cilia (CC) of photoreceptors, remain unclear. We used super-resolution fluorescence microscopy and electron microscopy to localize CEP290 in the CC and in the primary cilia of cultured cells with subdiffraction resolution and to determine effects of CEP290 deficiency in 3 mutant models. Radially, CEP290 localizes in close proximity to the microtubule doublets in the region between the doublets and the ciliary membrane. Longitudinally, it is distributed throughout the length of the CC whereas it is confined to the very base of primary cilia in human retinal pigment epithelium-1 cells. We found Y-shaped links, ciliary substructures between microtubules and membrane, throughout the length of the CC. Severe CEP290 deficiencies in mouse models did not prevent assembly of cilia or cause obvious mislocalization of ciliary components in early stages of degeneration. There were fewer cilia and no normal outer segments in the mutants, but the Y-shaped links were clearly present. These results point to photoreceptor-specific functions of CEP290 essential for CC maturation and stability following the earliest stages of ciliogenesis.

Using embedded alginate microparticles to tune the properties of in situ forming poly(N-isopropylacrylamide)-graft-chondroitin sulfate bioadhesive hydrogels for replacement and repair of the nucleus pulposus of the intervertebral disc.

Low back pain is a major public health issue associated with degeneration of the intervertebral disc (IVD). The early stages of degeneration are characterized by the dehydration of the central, gelatinous portion of the IVD, the nucleus pulposus (NP). One possible treatment approach is to replace the NP in the early stages of IVD degeneration with a hydrogel that restores healthy biomechanics while supporting tissue regeneration. The present study evaluates a novel thermosensitive hydrogel based on poly(N‐isopropylacrylamide‐graft‐chondroitin sulfate) (PNIPAAM‐g‐CS) for NP replacement. The hypothesis was tested that the addition of freeze‐dried, calcium crosslinked alginate microparticles (MPs) to aqueous solutions of PNIPAAm‐g‐CS would enable tuning of the rheological properties of the injectable solution, as well as the bioadhesive and mechanical properties of the thermally precipitated composite gel. Further, we hypothesized that the composite would support encapsulated cell viability and differentiation. Structure‐material property relationships were evaluated by varying MP concentration and diameter. The addition of high concentrations (50 mg/mL) of small MPs (20 ± 6 μm) resulted in the greatest improvement in injectability, compressive mechanical properties, and bioadhesive strength of PNIPAAm‐g‐CS. This combination of PNIPAAM‐g‐CS and alginate MPs supported the survival, proliferation, and differentiation of adipose derived mesenchymal stem cells toward an NP‐like phenotype in the presence of soluble GDF‐6. When implanted ex vivo into the intradiscal cavity of degenerated porcine IVDs, the formulation restored the compressive and neutral zone stiffnesses to intact values and resisted expulsion under lateral bending. Overall, results indicate the potential of the hydrogel composite to serve as a scaffold for supporting NP regeneration. This work uniquely demonstrates that encapsulation of re‐hydrating polysaccharide‐based MPs may be an effective method for improving key functional properties of in situ forming hydrogels for orthopedic tissue engineering applications.

Investigation of Somatic Mutations in Human Brains Targeting Genes Associated With Parkinson's Disease.

Background: Somatic single nucleotide variant (SNV) mutations occur in neurons but their role in synucleinopathies is unknown.Aim: We aimed to identify disease-relevant low-level somatic SNVs in brains from sporadic patients with synucleinopathies and a monozygotic twin carrying LRRK2 G2019S, whose penetrance could be explained by somatic variation.Methods and Results: We included different brain regions from 26 Parkinson's disease (PD), one Incidental Lewy body, three multiple system atrophy cases, and 12 controls. The whole SNCA locus and exons of other genes associated with PD and neurodegeneration were deeply sequenced using molecular barcodes to improve accuracy. We selected 21 variants at 0.33–5% allele frequencies for validation using accurate methods for somatic variant detection.Conclusions: We could not detect disease-relevant somatic SNVs, however we cannot exclude their presence at earlier stages of degeneration. Our results support that coding somatic SNVs in neurodegeneration are rare, but other types of somatic variants may hold pathological consequences in synucleinopathies.

Association of a Novel Intronic Variant in RPGR With Hypomorphic Phenotype of X-Linked Retinitis Pigmentosa

Pathogenic variants in retinitis pigmentosa GTPase regulator (RPGR) gene typically lead to a severe form of X-linked retinitis pigmentosa, which is associated with early severe vision loss. To investigate an X-linked retinal degeneration family with atypical preservation of visual acuity in the presence of a novel deep intronic splice site RPGR c.779-5T>G variant. In this case series, 3 members of an X-linked retinal degeneration family were studied by in-depth phenotyping and genetic screening at a single center. Data were collected and analyzed from November 2018 to March 2020. Data were collected on full ophthalmic history, examination, and retinal imaging. A full retinitis pigmentosa gene panel was analyzed by next-generation sequencing. The pathogenicity of the RPGR c.779-5T>G variant was assessed by in silico splice prediction tools and by purpose-designed in vitro splicing assay. An 84-year-old man was referred with clinical diagnosis of choroideremia and possible inclusion into a gene therapy trial. He presented with late-stage retinal degeneration and unusually preserved visual acuity (78 and 68 ETRDS letters) that clinically resembled choroideremia. His 23-year-old grandson was still in early stages of degeneration but showed a very different clinical picture, typical of retinitis pigmentosa. Next-generation sequencing identified a sole RPGR c.779-5T>G variant of undetermined pathogenicity in both cases. The daughter of the proband showed an RPGR carrier phenotype and was confirmed to carry the same variant. The molecular analysis confirmed that the RPGR c.779-5T>G variation reduced the efficiency of intron splicing compared with wild type, leading to a population of mutant and normal transcripts. The predicted consequences of the pathogenic variant are potential use of an alternative splice acceptor site or complete skipping of exon 8, resulting in truncated forms of the RPGR protein with different levels of glutamylation. These results support the importance of careful interpretation of inconsistent clinical phenotypes between family members. Using a molecular splicing assay, a new pathogenic variant in a noncoding region of RPGR was associated with a proportion of normal and hypomorphic RPGR, where cones are likely to survive longer than expected, potentially accounting for the preserved visual acuity observed in this family.

The shell gland in laying and natural moulting commercial egg-type chickens: A histomorphological and ultrastructural study.

The purpose of the present study was to determine the histological and ultrastructural changes in the luminal epithelium of the shell gland associated with natural moulting. Samples of the shell gland from laying (32weeks old) and moulting (75weeks old) hens were studied using histological, histochemical and electron microscopic techniques. In addition, TUNEL was used to demonstrate the distribution of apoptotic cells in the luminal epithelium of the shell gland. Autophagy, characterized by the presence of autophagosomes and autolysosomes, was evident in the early stages of degeneration in non-ciliated, ciliated and mitochondrial cells. The intermediate and advanced stages of regression in non-ciliated as well as mitochondrial cells occurred via apoptosis, while both apoptotic and necrotic ciliated cells were observed during the later stages of degeneration. The results of the present study suggest that a synergy of autophagy, apoptosis and necrosis is involved in the involution of the shell gland during natural moulting.

Visual responses in the dorsal lateral geniculate nucleus at early stages of retinal degeneration in rd1 PDE6β mice.

Inherited retinal degenerations encompass a wide range of diseases that result in the death of rod and cone photoreceptors, eventually leading to irreversible blindness. Low vision survives at early stages of degeneration, at which point it could rely on residual populations of rod/cone photoreceptors as well as the inner retinal photoreceptor, melanopsin. To date, the impact of partial retinal degeneration on visual responses in the primary visual thalamus (dorsal lateral geniculate nucleus, dLGN) remains unknown, as does their relative reliance on surviving rod and cone photoreceptors vs. melanopsin. To answer these questions, we recorded visually evoked responses in the dLGN of anesthetized rd1 mice using in vivo electrophysiology at an age (3-5 wk) at which cones are partially degenerate and rods are absent. We found that excitatory (ON) responses to light had lower amplitude and longer latency in rd1 mice compared with age-matched visually intact controls; however, contrast sensitivity and spatial receptive field size were largely unaffected at this early stage of degeneration. Responses were retained when those wavelengths to which melanopsin is most sensitive were depleted, indicating that they were driven primarily by surviving cones. Inhibitory responses appeared absent in the rd1 thalamus, as did light-evoked gamma oscillations in firing. This description of fundamental features of the dLGN visual response at this intermediate stage of retinal degeneration provides a context for emerging attempts to restore vision by introducing ectopic photoreception to the degenerate retina.NEW & NOTEWORTHY This study provides new therapeutically relevant insights to visual responses in the dorsal lateral geniculate nucleus during progressive retinal degeneration. Using in vivo electrophysiology, we demonstrate that visual responses have lower amplitude and longer latency during degeneration, but contrast sensitivity and spatial receptive fields remain unaffected. Such visual responses are driven predominantly by surviving cones rather than melanopsin photoreceptors. The functional integrity of this visual pathway is encouraging for emerging attempts at visual restoration.

The Origin of a New Sex Chromosome by Introgression between Two Stickleback Fishes.

Introgression is increasingly recognized as a source of genetic diversity that fuels adaptation. Its role in the evolution of sex chromosomes, however, is not well known. Here, we confirm the hypothesis that the Y chromosome in the ninespine stickleback, Pungitius pungitius, was established by introgression from the Amur stickleback, P. sinensis. Using whole genome resequencing, we identified a large region of Chr 12 in P. pungitius that is diverged between males and females. Within but not outside of this region, several lines of evidence show that the Y chromosome of P. pungitius shares a most recent common ancestor not with the X chromosome, but with the homologous chromosome in P. sinensis. Accumulation of repetitive elements and gene expression changes on the new Y are consistent with a young sex chromosome in early stages of degeneration, but other hallmarks of Y chromosomes have not yet appeared. Our findings indicate that porous species boundaries can trigger rapid sex chromosome evolution.

Comparative histomorphological and ultrastructural study of the luminal epithelium of the isthmus in laying and moulting domestic fowls (Gallus domesticus).

This study describes ciliated, nonciliated and mitochondrial luminal epithelial cells of the isthmus in laying and moulting domestic fowls using histological and ultrastructural techniques. The ciliated cells were nonsecretory, while numerous electron-dense secretory granules were present in the nonciliated cells of laying birds. Mitochondrial cells, occurring in two morphologically distinct forms, constituted the third type of epithelial cell present in the isthmus. The SEM study showed that the luminal epithelium was dominated by ciliated cells, the cilia of which partially obscured adjacent nonciliated cells. The involution of the luminal epithelium in moulting birds occurred via autophagy, apoptosis and necrosis. Autophagic inclusions, which included autophagosomes and autolysosomes, were present in the early degenerative phases of ciliated, nonciliated and mitochondrial cells. Nonciliated cells underwent degeneration via apoptosis, which was characterized by nuclear and cytoplasmic condensation. Apoptotic and necrotic ciliated cells were evident during the intermediate and advanced stages of regression. The presence of apoptotic cell death was confirmed using the TUNEL assay. Loss of cilia via the formation of cilia packets was observed using TEM and SEM. Necrotic cell death occurred in mitochondrial cells during the intermediate and late stages of degeneration. In conclusion, the findings of the study on isthmus involution in moulting birds suggest that autophagy is a process confined to the early stages of degeneration, while apoptosis and/or necrosis occur in the terminal stages of regression.

Ultrastructure of the tubular glands in the isthmus region of the oviduct in laying and natural moulting commercial egg-type chickens.

The study investigated the ultrastructural characteristics of tubular gland and duct cells, as well as luminal gland cells in the isthmus region of the oviduct of laying and natural moulting hens. Tubular glands in laying birds were composed of type 1 and 2 cells. Based on the preponderance of each cell type, in relation to the location of a developing egg in the oviduct of the domestic fowl, these gland cells may represent different functional states of the same cell. The findings of the study on natural moulting birds suggest that autophagy is a process confined to the early stages of degeneration, while necrosis occurs in the terminal stages.

Spectral analysis of fundus autofluorescence pattern as a tool to detect early stages of degeneration in the retina and retinal pigment epithelium.

The aim of this work is the determination of quantitative diagnostic criteria based on the spectral characteristics of fundus autofluorescence to detect early stages of degeneration in the retina and retinal pigment epithelium (RPE). RPE cell suspension samples were obtained from the cadaver eyes with and without signs of age-related macular degeneration (AMD). Fluorescence analysis at an excitation wavelength of 488 nm was performed. The fluorescence lifetimes of lipofuscin-granule fluorophores were measured by counting time-correlated photon method. Comparative analysis of fluorescence spectra of RPE cell suspensions from the cadaver eyes with and without signs of AMD showed a significant difference in fluorescence intensity at 530-580 nm in response to fluorescence excitation at 488 nm. It was notably higher in eyes with visual pathology than in normal eyes regardless of the age of the eye donor. Measurements of fluorescence lifetimes of lipofuscin fluorophores showed that the contribution of photooxidation and photodegradation products of bisretinoids to the total fluorescence at 530-580 nm of RPE cell suspensions was greater in eyes with visual pathology than in normal eyes. Because photooxidation and photodegradation products of bisretinoids are markers of photodestructive processes, which can cause RPE cell death and initiate degenerative processes in the retina, quantitative determination of increases in these bisretinoid products in lipofuscin granules may be used to establish quantitative diagnostic criteria for degenerative processes in the retina and RPE.

HIF-1α stabilization reduces retinal degeneration in a mouse model of retinitis pigmentosa.

Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by progressive and irreversible loss of vision due to rod and cone degeneration. Evidence suggests that an inappropriate oxygen level could contribute to its pathogenesis. Rod cell death could increase oxygen concentration, reduce hypoxia-inducible factor 1 (HIF-1α) and contribute to cone cell death. The purposes of this study were: 1) to analyze the temporal profile of HIF-1α, its downstream effectors VEGF, endothelin-1 (ET-1), iNOS, and glucose transporter 1 (GLUT1), and neuroinflammation in retinas of the murine model of rd10 ( retinal degeneration 10) mice with RP; 2) to study oxygen bioavailability in these retinas; and 3) to investigate how stabilizing HIF-1α proteins with dimethyloxaloglycine (DMOG), a prolyl hydroxylase inhibitor, affects retinal degeneration, neuroinflammation, and antioxidant response in rd10 mice. A generalized down-regulation of HIF-1α and its downstream targets was detected in parallel with reactive gliosis, suggesting high oxygen levels during retinal degeneration. At postnatal d 18, DMOG treatment reduced photoreceptor cell death and glial activation. In summary, retinas of rd10 mice seem to be exposed to a hyperoxic environment even at early stages of degeneration. HIF-1α stabilization could have a temporal neuroprotective effect on photoreceptor cell survival, glial activation, and antioxidant response at early stages of RP.-Olivares-González, L., Martínez-Fernández de la Cámara, C., Hervás, D., Millán, J. M., Rodrigo, R. HIF-1α stabilization reduces retinal degeneration in a mouse model of retinitis pigmentosa.

Optical Coherence Tomography: Is Really a New Biomarker for Alzheimer's Disease?

Introduction:Retinal ganglion cell (RGC) degeneration was histopathologically proved previously in Alzheimer's disease (AD) patients. In this study, we aimed to determine RGC degeneration in vivo using optical coherence tomography (OCT) in AD.Methods:Twenty-one mild-to-moderate AD patients and 25 cognitively healthy age-matched controls were enrolled in this case–control prospective study. All participants underwent OCT examination to assess peripapillary retinal nerve fiber layer (RNFL) thickness, macular volume, and thickness.Results:Foveal thickness and volume were significantly higher in AD patients than controls (P = 0.023 and P = 0.024, respectively). Compared to controls, peripapillary RNFL and other macular region measurements of AD patients were not statistically different (for all P > 0.05).Discussion:Increased foveal thickness and volume can be associated with the pathological changes in the early stages of degeneration These results differ from previous studies, but still confirm retinal degeneration in AD.Conclusion:With further OCT studies on large populations, OCT will be in clinical use for early diagnosis of AD.