amyloid-beta-peptides and Macular-Degeneration

Age-related macular degeneration (AMD) is a sight-threatening disease with limited treatment options. We investigated whether amyloid β

Topics: Amyloid beta-Peptides; Cell Line; Drug Evaluation, Preclinical; Drugs, Chinese Herbal; Humans; Macular Degeneration; Peptide Fragments; Pyroptosis; Retinal Pigment Epithelium

To investigate whether activation of the liver X receptors (LXRs) inhibits amyloid β. Confluent cultures of human primary RPE and ARPE-19 cells pretreated with 5 μΜ of TO901317 (TO90), a synthetic agonist of LXR, or vehicle were incubated with 1 μΜ of Aβ. A negative linear relationship between the Aβ. Activation of the LXRα-ABCA1 axis may alleviate Aβ

Topics: Amyloid beta-Peptides; Cell Line; Cell Survival; Cells, Cultured; Cellular Senescence; Cytokines; Epithelial Cells; Humans; Hydrocarbons, Fluorinated; Inflammation; Liver X Receptors; Macular Degeneration; NF-kappa B; Peptide Fragments; Retinal Pigment Epithelium; Sulfonamides

Age-related macular degeneration (AMD) is a progressive retinal neurodegenerative disorder characterized by extracellular deposits known as drusen. A major constituent of drusen deposits are Alzheimer disease-associated amyloid β (Aβ) peptides. To understand the etiology of Aβ proteostasis in AMD, we delivered recombinant adeno-associated virus (AAV) encoding Aβ42 and Aβ40 peptides fused to BRI2 protein by intraocular injection in C57BL/6J mice. Endogenous protease cleavage of such constructs leads to production of secreted Aβ42 and Aβ40 respectively. We demonstrate that overexpression of secreted Aβ40 or Aβ42 resulted in dramatic induction of drusen-like deposits by 2 months' post-injection. These drusen-like deposits were immunopositive for Aβ and complement proteins but did not stain for conventional amyloid dyes, such as Thioflavin S. Both injected cohorts showed gliosis and degenerative changes, though ERG responses were minimally affected. Intriguingly, simultaneous overexpression of BRI-Aβ40 or BRI-Aβ42 together resulted in dose-dependent and cumulative changes reminiscent of AMD type pathology - drusen-like deposits, severe reduction in ERG responses, photoreceptor cell loss and gliosis. Here, we have established a physiological model of Aβ containing deposits in wild-type mice that recapitulates major retinal pathophysiological features of AMD and will be instrumental in mechanistic understanding and development of therapeutic strategies against AMD.

Topics: Amyloid beta-Peptides; Animals; Dependovirus; Disease Models, Animal; Epithelial Cells; Humans; Macular Degeneration; Mice, Inbred C57BL; Peptide Fragments; Proteolysis; Retinal Pigment Epithelium; Transfection

Amyloid-beta (Aβ) is a hallmark component of age-related macular degeneration (AMD), which induces secretion of pro-inflammatory cytokines from retinal pigment epithelium (RPE). Previous studies have shown that p50/RelA (p65), a member of NF-κB family, is an essential pro-inflammatory transcription factor responding to Aβ

Topics: Amyloid beta-Peptides; Animals; Cells, Cultured; Electroretinography; Gene Expression Regulation; Inflammation; Macular Degeneration; Male; Mice; Mice, Inbred C57BL; NF-kappa B p50 Subunit; Peptide Fragments; Proto-Oncogene Proteins c-rel; Retinal Pigment Epithelium; RNA Interference; RNA, Small Interfering; Transcription Factor RelA; Transcription Factor RelB

Drusen are hallmarks of age-related macular degeneration (AMD). Amyloid-beta 1-40 (Aβ 1-40), a constituent of drusen, is known to stimulate inflammatory pathways in RPE; however, its effect in vivo is not known. The purpose of this study was to examine the effect of Aβ 1-40 on cytokine expression and inflammasome activation relevant to AMD in an animal model.. Wild-type rats received intravitreal injections of Aβ 1-40, and eyes were taken at days 1, 4, 14, and 49 postinjection. The RPE, neuroretina, and vitreous were analyzed for cytokine expression, inflammasome activation, and microglial response via RT-PCR, immunohistochemistry, and suspension array assay. Retinal cell loss was assessed via apoptotic markers and retinal thickness.. Aβ 1-40 stimulated upregulation of IL-6, TNF-α, IL-1β, IL-18, caspase-1, NLRP3, and XAF1 genes in the RPE/choroid and the neuroretina. Increased IL-1β and IL-6 immunoreactivity was found in retinal sections, and elevated levels of IL-1β and IL-18 were found in the vitreous of Aβ-injected eyes. Aβ 1-40 induced a moderate increase in CD11b/c-reactive cells on day 1 postinjection only. No evidence of the proapoptotic XAF1 protein, p53, TUNEL immunoreactivity, or retinal thinning was observed.. These results confirm earlier in vitro work and support the proinflammatory role of drusen component Aβ 1-40 in the RPE and retina. Inflammasome activation may be responsible for this effect in vivo. This model is useful for understanding cellular triggers of inflammasome activation and proposed early inflammatory events in the outer retina associated with the etiology of AMD.

Topics: Amyloid beta-Peptides; Animals; Cytokines; Disease Models, Animal; Immunohistochemistry; Inflammasomes; Intravitreal Injections; Macular Degeneration; Male; Microglia; Peptide Fragments; Rats; Rats, Long-Evans; Real-Time Polymerase Chain Reaction; Retina; Retinal Pigment Epithelium; Up-Regulation

Age-related macular degeneration (AMD) is the predominant cause of irreversible blindness in the elderly population. Despite intensive basic and clinical research, its pathogenesis remains unclear. However, evidence suggests that immunological and inflammatory factors contribute to the pathogenesis of AMD. A newly identified cytokine, IL-33, appears to be an important pro-inflammatory cytokine promoting tissue inflammation. In this study, IL-33 was increased through amyloid-beta(1-40) (Aβ(1-40)) stimulation and regulated inflammatory cytokines including IL-6, IL-8, IL-1β, and TNF-α secretion using different signaling pathways in retinal pigment epithelium (RPE) cells. Furthermore, ST2L, the important component of the IL-33 receptor, was significantly increased following recombinant human IL-33 stimulation in RPE cells. These findings suggest that IL-33-mediated inflammatory responses in RPE cells are involved in the pathogenesis of AMD. Greater understanding of the inflammatory effect of IL-33 and its role in RPE cells should aid the development of future clinical therapeutics and enable novel pharmacological approaches towards the prevention of AMD.

Topics: Amyloid beta-Peptides; Anthracenes; Butadienes; Cell Line; Humans; Imidazoles; Inflammation; Interleukin-1 Receptor-Like 1 Protein; Interleukin-1beta; Interleukin-33; Interleukin-6; Interleukin-8; Interleukins; JNK Mitogen-Activated Protein Kinases; Macular Degeneration; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; NF-kappa B; Nitriles; Peptide Fragments; Pyridines; Receptors, Cell Surface; Retinal Pigment Epithelium; Sulfones; Tumor Necrosis Factor-alpha

Age-related macular degeneration (AMD) is a leading cause of visual dysfunction worldwide. Amyloid β (Aβ) peptides, Aβ1-40 (Aβ40) and Aβ1-42 (Aβ42), have been implicated previously in the AMD disease process. Consistent with a pathogenic role for Aβ, we show here that a mouse model of AMD that invokes multiple factors that are known to modify AMD risk (aged human apolipoprotein E 4 targeted replacement mice on a high-fat, cholesterol-enriched diet) presents with Aβ-containing deposits basal to the retinal pigmented epithelium (RPE), histopathologic changes in the RPE, and a deficit in scotopic electroretinographic response, which is reflective of impaired visual function. Strikingly, these electroretinographic deficits are abrogated in a dose-dependent manner by systemic administration of an antibody targeting the C termini of Aβ40 and Aβ42. Concomitant reduction in the levels of Aβ and activated complement components in sub-RPE deposits and structural preservation of the RPE are associated with anti-Aβ40/42 antibody immunotherapy and visual protection. These observations are consistent with the reduction in amyloid plaques and improvement of cognitive function in mouse models of Alzheimer's disease treated with anti-Aβ antibodies. They also implicate Aβ in the pathogenesis of AMD and identify Aβ as a viable therapeutic target for its treatment.

Topics: Amyloid beta-Peptides; Animals; Antibodies, Bispecific; Apolipoprotein E4; Complement System Proteins; Dietary Fats; Disease Models, Animal; Dose-Response Relationship, Immunologic; Female; Humans; Immunotherapy; Macular Degeneration; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Mice, Transgenic; Peptide Fragments; Retinal Pigment Epithelium; Vision, Low

One of the earliest signs of age-related macular degeneration (AMD) is the formation of drusen which are extracellular deposits beneath the retinal pigmented epithelium (RPE). To investigate the relationship between drusen and AMD, we focused on amyloid beta (Abeta), a major component of drusen and also of senile plaques in the brain of Alzheimer's patients. We previously reported that Abeta was accumulated in drusen-like structure in senescent neprilysin gene-disrupted mice. The purpose of this study was to investigate the influence of Abeta on factor B, the main activator of the complement alternative pathway. The results showed that Abeta did not directly modulate factor B expression in RPE cells, but increased the production of monocyte chemoattractant protein-1 (MCP-1). Abeta also increased the production of IL-1beta and TNF-alpha in macrophages/microglia, and exposure of RPE cells to IL-1beta and TNF-alpha significantly up-regulated factor B. Co-cultures of RPE cells and macrophages/microglia in the presence of Abeta significantly increased the expression of factor B in RPE. These findings indicate that cytokines produced by macrophages/microglia that were recruited by MCP-1 produced in RPE cells stimulated by Abeta up-regulate factor B in RPE cells. Thus, a combined mechanism exists for Abeta-induced for the activation of the complement alternative pathway in the subretinal space; cytokine-induced up-regulation of activator factor B and dysfunction of the inhibitor factor I by direct binding to Abeta as suggested in our earlier study.

Topics: Amyloid beta-Peptides; Animals; Autocrine Communication; Cells, Cultured; Chemokine CCL2; Coculture Techniques; Complement Activation; Complement Factor B; Cytokines; Epithelial Cells; Humans; Interferon-gamma; Interleukin-1beta; Macrophages, Peritoneal; Macular Degeneration; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Neprilysin; Paracrine Communication; Peptide Fragments; Retinal Drusen; Retinal Pigment Epithelium; RNA, Messenger; Tumor Necrosis Factor-alpha; Up-Regulation