Alzheimer's disease (AD) is the most common form of dementia with progressive deterioration of memory and cognition. Complaints related to vision are common among AD patients. Several changes in the retina, lens, and in the vasculature have been noted in the AD eye that may be the cause of visual symptoms experienced by the AD patient. Anatomical changes have been detected within the eye before signs of cognitive impairment and memory loss are apparent. Unlike the brain, the eye is a unique organ that can be visualized noninvasively at the cellular level because of its transparent nature, which allows for inexpensive testing of biomarkers in a clinical setting. In this review, we have searched for candidate biomarkers that could enable diagnosis of AD, covering ocular neurodegeneration associated with functional tests. We explore the evidence that suggests that inexpensive, noninvasive clinical tests could be used to detect AD ocular biomarkers.
The molecular identification and localization of xCT and EAAT1 to -5 in the lens raises the possibility that in the outer cortex XC- and EAAT4/5 may work together to accumulate cysteine for GSH synthesis. The presence of xCT and the absence of the EAATs in the center of the lens suggest that XC- could operate with an alternative glutamate uptake pathway to accumulate cysteine where it can potentially act as a low-molecular-mass antioxidant.
Oxidative stress and the subsequent oxidative damage to lens proteins is a known causative factor in the initiation and progression of cataract formation, the leading cause of blindness in the world today. Due to the role of oxidative damage in the etiology of cataract, antioxidants have been prompted as therapeutic options to delay and/or prevent disease progression. However, many exogenous antioxidant interventions have to date produced mixed results as anti-cataract therapies. The aim of this review is to critically evaluate the efficacy of a sample of dietary and topical antioxidant interventions in the light of our current understanding of lens structure and function. Situated in the eye behind the blood-eye barrier, the lens receives it nutrients and antioxidants from the aqueous and vitreous humors. Furthermore, being a relatively large avascular tissue the lens cannot rely of passive diffusion alone to deliver nutrients and antioxidants to the distinctly different metabolic regions of the lens. We instead propose that the lens utilizes a unique internal microcirculation system to actively deliver antioxidants to these different regions, and that selecting antioxidants that can utilize this system is the key to developing novel nutritional therapies to delay the onset and progression of lens cataract.
Tissues in the anterior segment of the eye are particular vulnerable to oxidative stress. To minimise oxidative stress, ocular tissues utilise a range of antioxidant defence systems which include nonenzymatic and enzymatic antioxidants in combination with repair and chaperone systems. However, as we age our antioxidant defence systems are overwhelmed resulting in increased oxidative stress and damage to tissues of the eye and the onset of various ocular pathologies such as corneal opacities, lens cataracts, and glaucoma. While it is well established that nonenzymatic antioxidants such as ascorbic acid and glutathione are important in protecting ocular tissues from oxidative stress, less is known about the delivery mechanisms used to accumulate these endogenous antioxidants in the different tissues of the eye. This review aims to summarise what is currently known about the antioxidant transport pathways in the anterior eye and how a deeper understanding of these transport systems with respect to ocular physiology could be used to increase antioxidant levels and delay the onset of eye diseases.
Purpose
To optimize fixation, sectioning, and immunolabeling protocols to map the morphology of the human lens with confocal microscopy.
Methods
Transparent human lenses were fixed in 0.75% paraformaldehyde for 24 hours, cut in half, and fixed for another 24 hours. Lenses were cryoprotected, sectioned, and labeled with wheat germ agglutinin, aquaporin-0 antibodies, Hoechst, or toluidine blue. Before fixation, some lenses were incubated in an extracellular marker dye, Texas Red-dextran. Labeled sections were imaged with a confocal microscope. Overlapping images were tiled together to form a continuous image montage of fiber cell morphology from the periphery to the lens center.
Results
Fiber cell morphologies were identical with those previously described by electron microscopy and allowed immunohistochemistry to be performed for a representative membrane protein, aquaporin-0. Sectioning protocols enabled the epithelium and outer cortex to be retained, leading to the identification of two unique morphologic zones. In the first zone, an age-independent compaction of nucleated fiber cells and the initiation of extensive membrane remodeling occur. In the second zone, fiber cells retain their interdigitations but lose their nuclei, exhibit a distorted shape, and are less compressed. These zones are followed by the adult nucleus, which is marked by extensive compaction and a restriction of the extracellular space to the diffusion of Texas Red-dextran.
Conclusions
The authors have developed sectioning and imaging protocols to capture differentiation-dependent changes in fiber cell morphology and protein expression throughout the human lens. Results reveal that differentiating fiber cells undergo extensive membrane remodeling before their internalization into the adult nucleus.
The mapping of GSH and its precursor amino acids has shown that an alternative glycine uptake pathway exists in mature fiber cells. Although GLYT1 and -2 are likely to mediate glycine uptake in cortical fiber cells, GLYT2 alone appears responsible for the accumulation of glycine in the center of the lens. Enhancing the delivery of glycine to the core via the sutures may represent a pathway to protect the lens against the protein modifications associated with age-related nuclear cataract.
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