Glial remodeling and neural plasticity in human retinal detachment with proliferative vitreoretinopathy.

PURPOSE: To investigate glial remodeling and neuronal plasticity in adult human retinal detachment complicated by proliferative vitreoretinopathy (PVR) and to grade pathologic changes with a severity scoring system. METHODS: Sixteen full-thickness retinectomy specimens obtained at retinal relaxing surgery for PVR were fixed in 4% paraformaldehyde immediately after excision and compared to similarly processed normal donor retinas. Agarose-embedded sections (100-microm-thick) were double labeled for immunohistochemistry by confocal microscopy, with antibodies against rod opsin and GFAP; vimentin and M/L-cone opsin; calbindin D and S-cone opsin; and cytochrome oxidase and synaptophysin. These staining patterns formed the basis of a retinal pathology scoring system, and immunohistochemistry was also used to detect CD68, neurofilaments, protein kinase C, growth-associated protein-43, and a pan-cone-specific enzymatic marker. Morphology was also assessed by light microscopy of resin-embedded semithin sections. RESULTS: Prolonged detachment was characterized by photoreceptor degeneration and intracellular redistribution of opsin proteins to the plasma membrane in the outer nuclear layer (ONL). Remodeling of rod synaptic terminals was characterized by terminal retraction and also by axon extension to the inner retina in most specimens. Rod bipolar cell dendrites extended into the ONL, as did fine, horizontal cell processes. Large ganglion cells showed upregulated neurofilament and GAP-43 expression, with neurites sprouting from somata and axon collaterals. Anti-cytochrome oxidase labeling of surviving inner segments was reduced but detectable in all specimens, as was anti-calbindin D labeling of horizontal and amacrine cells. All specimens demonstrated a marked upregulation of Muller cell and astrocyte expression of GFAP and vimentin. More severe degenerative changes correlated with trauma and prolonged detachment duration when scored according to this system. CONCLUSIONS: The neural and glial components of detached neurosensory retina complicated by PVR exhibit pathology that changes characteristically with increasing detachment severity. Even in advanced degeneration, most of the structural motifs necessary for functional recovery are retained. Evidence of remodeling in the first-, second-, and third-order neurons of detached adult human retina may represent an attempt to re-establish synaptic connectivity.

The ability of rapid retinal reattachment to stop or reverse the cellular and molecular events initiated by detachment.

PURPOSE: To determine the effects of reattachment on the molecular and cellular events initiated by a retinal detachment lasting 1 hour or 1 day. METHODS: Experimental retinal detachments were created in the right eyes of nine cats. Reattachments were performed 1 hour (n = 3) or 1 day (n = 3) after the detachment, and the animals were killed 3 days after detachment. Three-day detached (n = 3) and normal (n = 3) retinas were used for comparisons. Agarose-embedded sections were double labeled with a panel of antibodies. Some sections were also probed with the TUNEL technique to detect apoptotic cells. Wax-embedded sections were labeled with the MIB-1 antibody to the Ki67 protein to detect proliferating cells. RESULTS: The 1-hour and 1-day detachments followed by reattachment showed a very similar and consistent reduction in photoreceptor deconstruction and the Müller cell gliotic response when compared with 3-day retinal detachments without reattachment. Light microscopy and immunolabeling with opsin antibodies showed a significant reduction in both rod and cone outer segment (OS) degeneration, even though OS length was shorter than normal. The reattachments also showed a reduction in opsin redistribution, retraction of rod terminals, TUNEL-labeled photoreceptors, loss of cytochrome oxidase staining in photoreceptors, neurite outgrowth from second-order neurons, the number of proliferating cells, and the increase in intermediate filaments and loss of soluble proteins from Müller cells. The apparent re-ensheathing of the OS by the apical processes of the retinal pigment epithelium had begun but was not completely normal. CONCLUSIONS: These data indicate that, even though the length of the OS is less than normal, retinal reattachment within 1 day of detachment can either greatly retard or reverse many of the molecular and cellular changes initiated by detachment.

The Alzheimer's A beta -peptide is deposited at sites of complement activation in pathologic deposits associated with aging and age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in older individuals worldwide. The disease is characterized by abnormal extracellular deposits, known as drusen, that accumulate along the basal surface of the retinal pigmented epithelium. Although drusen deposition is common in older individuals, large numbers of drusen and/or extensive areas of confluent drusen represent a significant risk factor for AMD. Widespread drusen deposition is associated with retinal pigmented epithelial cell dysfunction and degeneration of the photoreceptor cells of the neural retina. Recent studies have shown that drusen contain a variety of immunomodulatory molecules, suggesting that the process of drusen formation involves local inflammatory events, including activation of the complement cascade. Similar observations in Alzheimer's disease (AD) have lead to the hypothesis that chronic localized inflammation is an important element of AD pathogenesis, with significant neurodegenerative consequences. Accordingly, the amyloid beta (A beta) peptide, a major constituent of neuritic plaques in AD, has been implicated as a primary activator of complement in AD. Here we show that A beta is associated with a substructural vesicular component within drusen. A beta colocalizes with activated complement components in these "amyloid vesicles," thereby identifying them as potential primary sites of complement activation. Thus, A beta deposition could be an important component of the local inflammatory events that contribute to atrophy of the retinal pigmented epithelium, drusen biogenesis, and the pathogenesis of AMD.