The development of the devastating neurodegenerative condition, Alzheimer's disease, is strongly associated with amyloid-␤ (A␤) deposition, neuronal apoptosis, and cell loss. Here, we provide evidence that implicates these same mechanisms in the retinal disease glaucoma, a major cause of irreversible blindness worldwide, previously associated simply with the effects of intraocular pressure. We show that A␤ colocalizes with apoptotic retinal ganglion cells (RGC) in experimental glaucoma and induces significant RGC apoptosis in vivo in a dose-and time-dependent manner. We demonstrate that targeting different components of the A␤ formation and aggregation pathway can effectively reduce glaucomatous RGC apoptosis in vivo, and finally, that combining treatments (triple therapy) is more effective than monotherapy. Our work suggests that targeting the A␤ pathway provides a therapeutic avenue in glaucoma management. Furthermore, our work demonstrates that the combination of agents affecting multiple stages in the A␤ pathway may be the most effective strategy in A␤-related diseases.combination therapy ͉ neuroprotection ͉ retinal ganglion cell apoptosis A lthough glaucoma, a major cause of blindness worldwide (1), is commonly linked to raised intraocular pressure (IOP) (2), the precise means by which IOP may lead to the irreversible destruction of retinal ganglion cells (RGCs, which are the nerve cells that transfer visual information from the eye to the brain) is far from clear. Indeed, interpretation of the mechanism is further complicated by the fact that damage can also occur at low IOP. Thus, for example, recent evidence indicates progressive visual-field loss in patients despite normalization of IOP with pressure-lowering treatment strategies (3, 4), which means that an alternative approach to the treatment of glaucoma is urgently needed. The principal step leading to irreversible loss of vision in glaucoma is RGC apoptosis, and the question is what mechanisms precede this cell death. Raised IOP in experimental glaucoma models can clearly precipitate RGC apoptosis (5-7) whatever the actual intervening steps. However, the presence of progressive glaucomatous damage in patients with normalized IOP has focused a growing body of work on alternative strategies to those regulating IOP and especially approaches targeting the cellular mechanisms leading to apoptosis.Amyloid-␤ (A␤) is the major constituent of senile plaques in Alzheimer's disease (AD), the formation of which, caused by abnormal processing of amyloid precursor protein (APP), has been involved in AD neuropathology, although the proximate cause of the neurodegeneration responsible for cognitive impairment is not clear (8). A␤ has recently been reported to be implicated in the development of RGC apoptosis in glaucoma, with evidence of caspase-3-mediated abnormal APP processing and increased expression of A␤ in RGCs in experimental glaucoma (9) and decreased vitreous A␤ levels (consistent with retinal A␤ deposition) in patients with glaucoma (10). Further evidenc...

Apoptotic nerve cell death is implicated in the pathogenesis of several devastating neurodegenerative conditions, including glaucoma and Alzheimer's and Parkinson's diseases. We have devised a noninvasive real-time imaging technique using confocal laserscanning ophthalmoscopy to visualize single nerve cell apoptosis in vivo, which allows longitudinal study of disease processes that has not previously been possible. Our method utilizes the unique optical properties of the eye, which allow direct microscopic observation of nerve cells in the retina. We have been able to image changes occurring in nerve cell apoptosis over hours, days, and months and show that effects depend on the magnitude of the initial apoptotic inducer in several models of neurodegenerative disease in rat and primate. This technology enables the direct observation of single nerve cell apoptosis in experimental neurodegeneration, providing the opportunity for detailed investigation of fundamental disease mechanisms and the evaluation of interventions with potential clinical applications, together with the possibility of taking this method through to patients.A poptosis is an orchestrated form of cell ''death by suicide.'' It is essential in both the development and normal maintenance of tissue function. It is also implicated in the pathology of a number of severe neurodegenerative disorders such as glaucoma, motor neuron, and Alzheimer's, Parkinson's, and Huntington's diseases (1). There is evidence that a similar pathogenesis may contribute to neurodegenerative processes in these conditions (2), and that the extent of nerve cell loss is correlated with functional deficit (3-6). If we could directly visualize this process, it would facilitate a much more precise diagnosis and critically enable accurate tracking of the disease state and the action of therapy. However, until now, it has not been possible to detect nerve cell apoptosis in vivo (1, 7-10).Annexin 5 is a protein that, in the presence of Ca 2ϩ , has a high affinity for phosphatidylserine (PS), an anionic phospholipid that is enriched in the inner leaflet of plasma membranes. The externalization of PS from the inner leaflet to the outer layer of the cell membrane is an invariant early feature in the apoptotic process that occurs before DNA fragmentation and nuclear condensation. Because of its properties, FITC-annexin 5 has become widely used in the cytological detection of cells undergoing apoptosis (11). More recently, annexin 5 has been shown to be effective in the identification of apoptosis in vivo by using radiological and macroscopic fluorescent techniques (7,8,10,12,13).However, existing in vivo techniques using annexin 5 either have been unable to resolve the process to a single cellular level (7-9) or require an invasive method performed under terminal anesthesia (10). Imaging the eye, compared with the rest of the body, offers a unique opportunity because of the presence of clear optical media allowing direct visualization of labeled disease processes as they occur. This mea...

The results demonstrated that RGC apoptosis in glaucoma correlates strongly with elevated IOP and is significantly associated with IOP-induced changes in specific ECM components in the RGC layer. The study shows for the first time a link between MMP-9, laminin degradation, RGC apoptosis, and IOP exposure in glaucoma. The findings suggest that abnormal ECM remodeling in the glaucomatous retina may relate to RGC death and support the notion that the retina is a primary site of injury in glaucoma.

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These findings suggest that the lack of Ccl2 leads to a monocyte/macrophage-trafficking defect during aging and to an impaired recruitment of these cells to sites of laser injury. Other, previously described features of Ccl2(-/-) mice that are similar to AMD may be the result of aging alone.

Various phenotypic patterns of abnormal FAF can be identified with cSLO imaging. Distinct patterns may reflect heterogeneity at a cellular and molecular level in contrast to a nonspecific aging process. The results indicate that the classification system yields a relatively high degree of intra- and interobserver agreement. It may be applicable for determination of novel prognostic determinants in longitudinal natural history studies, for identification of genetic risk factors, and for monitoring of future therapeutic interventions to slow the progression of early AMD.

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