Lysosomes are highly dynamic, single membranebound compartments that are critical for maintaining cellular homeostasis. These organelles, which appear to vary between 200 nm–1 μm in diameter, originate from the matu...Lysosomes are highly dynamic, single membranebound compartments that are critical for maintaining cellular homeostasis. These organelles, which appear to vary between 200 nm–1 μm in diameter, originate from the maturation of endocytic vesicles and via the enrichment of newly synthesized lysosomal proteins in the trans-Golgi network.展开更多
e-related macular degeneration （AMD） causes irreversible loss of central vision for which there is no effective treatment. Incipient pathology is thought to occur in the retina for many years before AMD manifests fr...e-related macular degeneration （AMD） causes irreversible loss of central vision for which there is no effective treatment. Incipient pathology is thought to occur in the retina for many years before AMD manifests from midlife onwards to affect a large proportion of the elderly. Although genetic as well as non-genetic/environmental risks are recognized, its complex aetiology makes it difficult to identify susceptibility, or indeed what type of AMD develops or how quickly it progresses in different individuals. Here we summarize the literature describing how the Alzheimer＇s-linked amyloid beta （Aβ） group of misfolding proteins accumulate in the retina. The discovery of this key driver of Alzheimer＇s disease in the senescent retina was unexpected and surprising, enabling an altogether different perspective of AMD. We argue that Aβ fundamentally differs from other substances which accumulate in the ageing retina, and discuss our latest findings from a mouse model in which physiological amounts of Aβ were subretinally-injected to recapitulate salient features of early AMD within a short period. Our discoveries as well as those of others suggest the pattern of Aβ accumulation and pathology in donor aged/AMD tissues are closely reproduced in mice, including late-stage AMD phenotypes, which makes them highly attractive to study dynamic aspects of Aβ-mediated retinopathy. Furthermore, we discuss our findings revealing how Aβ behaves at single-cell resolution, and consider the long-term implications for neuroretinal function. We propose Aβ as a key element in switching to a diseased retinal phenotype, which is now being used as a biomarker for latestage AMD.展开更多
Advances in imaging have led to the development of several new types of microscopes such as serial block face scanning electron microscopy (SBF-SEM),lightsheet microscopy,as well as X-ray micro-computed tomography (mi...Advances in imaging have led to the development of several new types of microscopes such as serial block face scanning electron microscopy (SBF-SEM),lightsheet microscopy,as well as X-ray micro-computed tomography (micro-CT),which enables the study of samples in fundamentally different ways.展开更多
基金Ph D Studentships from the Macular Society,Biotechnology and Biological Sciences Research Council (BBSRC) So Co Bio-DTPfunding from the Gi?t of Sight Appeal。
文摘Lysosomes are highly dynamic, single membranebound compartments that are critical for maintaining cellular homeostasis. These organelles, which appear to vary between 200 nm–1 μm in diameter, originate from the maturation of endocytic vesicles and via the enrichment of newly synthesized lysosomal proteins in the trans-Golgi network.
基金funded by the National Centre for the Replacement Refinement&Reduction of Animals in Research(NC3R:Grant#NC/L001152/1)the Macular Society,UK,National Eye Research Centrethe Gift of Sight Appeal
文摘e-related macular degeneration （AMD） causes irreversible loss of central vision for which there is no effective treatment. Incipient pathology is thought to occur in the retina for many years before AMD manifests from midlife onwards to affect a large proportion of the elderly. Although genetic as well as non-genetic/environmental risks are recognized, its complex aetiology makes it difficult to identify susceptibility, or indeed what type of AMD develops or how quickly it progresses in different individuals. Here we summarize the literature describing how the Alzheimer＇s-linked amyloid beta （Aβ） group of misfolding proteins accumulate in the retina. The discovery of this key driver of Alzheimer＇s disease in the senescent retina was unexpected and surprising, enabling an altogether different perspective of AMD. We argue that Aβ fundamentally differs from other substances which accumulate in the ageing retina, and discuss our latest findings from a mouse model in which physiological amounts of Aβ were subretinally-injected to recapitulate salient features of early AMD within a short period. Our discoveries as well as those of others suggest the pattern of Aβ accumulation and pathology in donor aged/AMD tissues are closely reproduced in mice, including late-stage AMD phenotypes, which makes them highly attractive to study dynamic aspects of Aβ-mediated retinopathy. Furthermore, we discuss our findings revealing how Aβ behaves at single-cell resolution, and consider the long-term implications for neuroretinal function. We propose Aβ as a key element in switching to a diseased retinal phenotype, which is now being used as a biomarker for latestage AMD.
基金supported by the Awards to JAR from the UK Macular Society,UKRI Quality Research Strategic Priorities Fund from Public Policy Southampton (New Things Fund) as well as the Gift of Sight Appeal。
文摘Advances in imaging have led to the development of several new types of microscopes such as serial block face scanning electron microscopy (SBF-SEM),lightsheet microscopy,as well as X-ray micro-computed tomography (micro-CT),which enables the study of samples in fundamentally different ways.
