Age-Related Macular Degeneration and the Other Double Helix The Cogan Lecture

Ambati, Jayakrishna

doi:10.1167/iovs.11-7328

Cited by 23 publications

(22 citation statements)

References 49 publications

(27 reference statements)

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“…Although many, or most, of the 48 correlated genes populating this category (see Supplemental Table 3) have roles in development and growth of other tissue types, all have also been linked to vasculature development. While the functional significance of this is difficult to discern at present, it may be relevant that angiogenesis is a well-established co-factor in tumor growth, and plays a key role in retinal macular degeneration (Ambati, 2011). …”

Section: Discussionmentioning

confidence: 99%

Microarray analyses of laser-captured hippocampus reveal distinct gray and white matter signatures associated with incipient Alzheimer's disease

Blalock

Buechel

Popović

et al. 2011

Journal of Chemical Neuroanatomy

187

152

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Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that threatens to reach epidemic proportions as our population ages. Although much research has examined molecular pathways associated with AD, relatively few such studies have focused on the disease’s critical early stages. In a prior microarray study we correlated gene expression in hippocampus with degree of Alzheimer’s disease and found close associations between upregulation of apparent glial transcription factor/epigenetic/tumor suppressor genes and incipient AD. The results suggested a new model in which AD pathology spreads along myelinated axons (Blalock et al., 2004). However, the microarray analyses were performed on RNA extracted from frozen hand-dissected hippocampal CA1 tissue blocks containing both gray and white matter, limiting the confidence with which transcriptional changes in gray matter could be distinguished from those in white matter. Here, we used laser capture microdissection (LCM) to exclude major white matter tracts while selectively collecting CA1 hippocampal gray matter from formalin-fixed, paraffin-embedded (FFPE) hippocampal sections of the same subjects assessed in our prior study. Microarray analyses of this gray matter-enriched tissue revealed many transcriptional changes similar to those seen in our past study and in studies by others, particularly for downregulated neuron-related genes. Additionally, the present analyses identified several previously undetected pathway alterations, including downregulation of molecules that stabilize ryanodine receptor Ca2+ release and upregulation of vasculature development. Conversely, we found a striking paucity of the upregulated changes in the putative glial and growth-related genes that had been strongly overrepresented in the prior mixed-tissue study. We conclude that FFPE tissue can be a reliable resource for microarray studies of brain tissue, that upregulation of growth-related epigenetic/transcription factors during incipient AD is predominantly localized in and around white matter (supporting our prior findings and model), and that novel alterations in vascular and ryanodine receptor-related pathways in gray matter are closely associated with incipient AD.

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Section: Discussionmentioning

confidence: 99%

Microarray analyses of laser-captured hippocampus reveal distinct gray and white matter signatures associated with incipient Alzheimer's disease

Blalock

Buechel

Popović

et al. 2011

Journal of Chemical Neuroanatomy

187

152

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“…AMD is the leading cause of irreversible vision loss in modern Western societies among adults over 50 and is projected to impact the lives of nearly 200 million people worldwide by the year 2020 (1)(2)(3)(4). It presents in two distinct forms, based on the types of lesions that occur in the late stages.…”

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confidence: 99%

MicroRNA-processing Enzymes Are Essential for Survival and Function of Mature Retinal Pigmented Epithelial Cells in Mice

Sundermeier¹,

Sakami²,

Sahu

et al. 2017

Journal of Biological Chemistry

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Edited by Paul E. FraserAge-related macular degeneration (AMD) is a major cause of irreversible vision loss. The neovascular or "wet" form of AMD can be treated to varying degrees with anti-angiogenic drugs, but geographic atrophy (GA) is an advanced stage of the more prevalent "dry" form of AMD for which there is no effective treatment. Development of GA has been linked to loss of the microRNA (miRNA)-processing enzyme DICER1 in the mature retinal pigmented epithelium (RPE). This loss results in the accumulation of toxic transcripts of Alu transposable elements, which activate the NLRP3 inflammasome and additional downstream pathways that compromise the integrity and function of the RPE. However, it remains unclear whether the loss of miRNA processing and subsequent gene regulation in the RPE due to DICER1 deficiency also contributes to RPE cell death. To clarify the role of miRNAs in RPE cells, we used two different mature RPE cell-specific Cre recombinase drivers to inactivate either Dicer1 or DiGeorge syndrome critical region 8 (Dgcr8), thus removing RPE miRNA regulatory activity in mice by disrupting two independent and essential steps of miRNA biogenesis. In contrast with prior studies, we found that the loss of each factor independently led to strikingly similar defects in the survival and function of the RPE and retina. These results suggest that the loss of miRNAs also contributes to RPE cell death and loss of visual function and could affect the pathology of dry AMD. Age-related macular degeneration (AMD)3 is a progressive retinal degenerative disorder that preferentially impacts the macula, the central region of the retina primarily responsible for both color vision and visual acuity. AMD is the leading cause of irreversible vision loss in modern Western societies among adults over 50 and is projected to impact the lives of nearly 200 million people worldwide by the year 2020 (1-4). It presents in two distinct forms, based on the types of lesions that occur in the late stages. The neovascular or "wet" form of AMD is associated with abnormal growth of blood vessels in the choriocapillaris, which extend through Bruch's membrane and cause acute vision loss that can be reversed relatively rapidly through intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors (5-8). In contrast, the dry form of AMD is characterized by a large number of drusen and occasionally by geographic atrophy (GA), the regional loss of macular photoreceptors, retinal pigmented epithelium (RPE), and choriocapillaris. These changes cause deficits in dark adaptation, along with dense visual field scotomas and a gradual decline in visual acuity (9 -11). Currently, there is no effective treatment for the dry form of AMD.Discovered over 2 decades ago in Caenorhabditis elegans, miRNAs regulate gene expression at the post-transcriptional level (12, 13). miRNA biogenesis involves two sequential cleavage steps. The first is accomplished in the nucleus by the microprocessor complex and involves a member of the ribonucleas...

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“…TLR3 and 7 are reportedly expressed in tissues and cells involved in the pathogenesis of AMD, including the RPE, macrophages, dendritic cells, as well as neural tissue (Ambati et al, 2003;Hageman et al, 2001;Kumar et al, 2004;Lee et al, 2007;Prehaud et al, 2005;Tsutsumi et al, 2003). Although it has been suggested that TLR3 variations may be associated with GA and CNV (Ambati, 2011;Kleinman et al, 2012;Yang et al, 2008) such association and those of TLR4 and 7 with AMD are not supported by Fig. 5.…”

Section: Discussionmentioning

confidence: 92%

“…TLRs have been associated with a number of ocular vascular and inflammatory diseases. TLR3 variations are associated with geographic atrophy (GA) and choroidal neovascularisation (CNV) (Ambati, 2011;Yang et al, 2008). Klettner et al (2013) reported the induction of cell death in RPE cells by TLR3 activation as a possible mechanism of GA.…”

Section: Introductionmentioning

confidence: 99%

Expression of Toll-like receptors in human retinal and choroidal vascular endothelial cells

Stewart

Wei

Branch

et al. 2015

Experimental Eye Research

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Age-Related Macular Degeneration and the Other Double Helix The Cogan Lecture

Cited by 23 publications

References 49 publications

Microarray analyses of laser-captured hippocampus reveal distinct gray and white matter signatures associated with incipient Alzheimer's disease

Microarray analyses of laser-captured hippocampus reveal distinct gray and white matter signatures associated with incipient Alzheimer's disease

MicroRNA-processing Enzymes Are Essential for Survival and Function of Mature Retinal Pigmented Epithelial Cells in Mice

Expression of Toll-like receptors in human retinal and choroidal vascular endothelial cells

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