Eyeworld

EW NEWS & OPINION 34 March 2017 Research highlight by Liz Hillman EyeWorld Staff Writer "It's still going on at the level of cells and molecules, but because our eyes and brains are so well-equipped to compensate and overlook defects, we have good vision, good hand-eye coordination, we won't notice," Dr. Ratnayaka said. Changes in the reti- nal neurofibrillary layer or detecting the retinal Ab1-42 load could be used as biomarkers for early disease. At this point, Dr. Ratnayaka said a reliable dye needs to be developed for in-vivo evaluation of retinal Ab so these assessments can be carried out non-invasively, similar to the way that retinal bleeding is imaged by funduscopy. While much of AMD research has focused on identifying genetic risk factors, Dr. Ratnayaka said the work being done with Ab proteins in AMD, in aged human retinas, and in mouse models is showing that non-genetic factors are also at play in driving disease. It has been known for some time that non-genetic factors such as diet and lifestyle affect the chances of devel- oping AMD. It is important these are addressed as well. "I think it is critical to first understand the underlying causes of AMD as this means that more effective treatments will then be de- veloped. A better understanding of this disease may provide new ways of identifying people who are at risk early on, perhaps before symptoms manifest. For example, individuals at risk could perhaps change their diet, start taking supplements, or stop smoking. Aging is something we cannot prevent, however much we would like to, but we can try to tilt the scales away from disease to a healthier retina. The ultimate thing is finding something to prevent AMD all together," Dr. Ratnayaka said. EW Reference 1. Taylor-Walker G, et al. The Alzheimer's-re- lated amyloid beta peptide is internalised by R28 neuroretinal cells and disrupts the microtubule associated protein 2 (MAP-2). Exp Eye Res. 2016;153:110–121. Editors' note: Dr. Ratnayaka has no financial interests related to his comments. Contact information Ratnayaka: J.Ratnayaka@soton.ac.uk we haven't quite looked at yet," Dr. Ratnayaka said. The investigators then injected Ab into mouse eyes to determine how likely is Ab to impair MAP-2 in the living retina?" "When retinas were analyzed af- ter 8 days, distinct areas correspond- ing to focal Ab deposits were ob- served in retinal ganglion cells, the inner nuclear and outer plexiform layers in addition to subretinal Ab aggregates. The accumulation within Ab within these retinal layers sup- ported the realistic possibility that MAP-2 activity in axons/dendrites of the retinal ganglion cells, bipolar, horizontal and photoreceptors may be targeted by Ab," Taylor-Walker et al. wrote. This research could have implications on diagnostics, esti- mating patient risk, identifying new therapies or preventative measures, and understanding different AMD phenotypes. In the case of macular degen- eration, the disease is either self-re- ported at the onset of visual impair- ment or a patient is identified as at risk due to the presence of drusen. But ahead of those scenarios, that doesn't mean the disease hasn't kickstarted. aptic plasticity and possibly lead to impaired function of retinal neurons and a subsequent diseased state. "Neurons are quite dynamic. They change shape, change their structure, change the point where their synapses are, how they com- municate from one neuron to another," Dr. Ratnayaka said, noting that this is how neurons in the brain behave and that he expects neurons of the retina to behave in a similar way. "If retinal neurons, for in- stance, cannot alter shape, form new synapses, or dismantle unused syn- apses because of defects in proteins such as MAP-2, then perhaps we start to get insights into how subtle disease effects begin to develop in the retina." Observing that MAP-2 was upregulated again after 48 hours, Dr. Ratnayaka speculated this could be indicative of two things. One could be that retinal neurons are trying to compensate for the damage done by Ab1-42, upregulating and restoring MAP-2. The second possibility is that Ab1-42 could be moving on to damage something else. "What we saw is, in fact, that could be the effect as far as MAP-2 is concerned, but it could be doing lasting damage to other things that Research identifies how amyloid beta proteins associated with Alzheimer's disease could affect retinal neurons W hile there is a growing body of research link- ing Alzheimer's-relat- ed, amyloid beta (Ab) proteins to age-related macular degeneration (AMD) and aging retinas in general, it was un- clear just how Ab proteins affected retinal neurons. Research from the University of Southampton, United Kingdom, sought to better understand this relationship and now suggests a new molecular pathway by which Ab proteins are impacting the neu- roretina. To study this, the investigators used R28 neuroretina cells. Ab—spe- cifically oligomeric Ab1-42, which is described as "the most cytotoxic and aggregate-prone" in the Ab family— was found to be internalized by R28 cells within just 24 hours and re- mained trapped intracellularly for 72 hours. During this period, Ab that were not internalized were observed to accumulate outside neurons. 1 Furthermore, R28 cultures exposed to Ab1-42 showed a 33% reduction of microtubule-associated protein 2 (MAP-2) expression. After 48 hours, however, the researchers observed that MAP-2 levels had recovered. "Using some of the evidence we've seen as to how Alzheimer's disease works and how Ab damages neurons in the brain, we thought, let's look at how that might pan out if you look at retinal neurons," said J. Arjuna Ratnayaka, PhD, lecturer, vision sciences, University of Southampton, and lead author of the study. "What we saw were these amyloid beta oligomers going into retinal neurons very quickly. That was surprising in the sense that if the proteins are there in human eyes as people get older, you might think the effect would be very gradual, but the fact that they go in quickly indi- cates they might start driving early disease, which we're only starting to understand." As for the effect of Ab1-42 on MAP-2 activity, Dr. Ratnayaka explained that this could affect syn- Alzheimer's-related proteins could be causing age-related macular degeneration

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