The potential role of amyloid   in the pathogenesis of age-related macular degeneration

Yoshida, Takeshi; Ohno‐Matsui, Kyoko; Ichinose, Shizuko; Sato, Toshio; Iwata, Nobuhisa; Saido, Takaomi C.; Hisatomi, Toshio; Mochizuki, Manabu; Morita, Ikuo

doi:10.1172/jci24635

Cited by 195 publications

(166 citation statements)

References 62 publications

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“…This implies that similar mechanisms may be responsible for plaque formation in Alzheimer disease and drusen formation in dry AMD. These results are consistent with the hypothesis that A␤ is associated with the pathogenesis of AMD (47).…”

Section: Discussionsupporting

confidence: 93%

Pigment Epithelium-derived Factor Maintains Retinal Pigment Epithelium Function by Inhibiting Vascular Endothelial Growth Factor-R2 Signaling through γ-Secretase

Ablonczy

Prakasam

Fant

et al. 2009

Journal of Biological Chemistry

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Wet age-related macular degeneration (AMD) attacks the integrity of the retinal pigment epithelium (RPE) barrier system. The pathogenic process was hypothesized to be mediated by vascular endothelial growth factor (VEGF) and antagonized by pigment epithelium-derived factor (PEDF). To dissect these functional interactions, monolayer cultures of RPE cells were established, and changes in transepithelial resistance were evaluated after administration of PEDF, placenta growth factor (VEGF-R1 agonist), and VEGF-E (VEGF-R2 agonist). A recently described mechanism of VEGF inhibition in endothelia required the release of VEGF-R1 intracellular domain by ␥-secretase. To evaluate this pathway in the RPE, cells were pretreated with inhibitors DAPT or LY411575. Processing of VEGF receptors was assessed by Western blot analysis. Administration of VEGF-E rapidly increased RPE permeability, and PEDF inhibited the VEGF-E response dose-dependently. Both ␥-secretase antagonists prevented the inhibitory effects of PEDF. The co-administration of PEDF and VEGF-E depleted the amount of VEGF-R2 in the membrane and increased the amount of VEGF-R2 ectodomain in the media. Therefore, the inhibitory effect of PEDF appears to be mediated via the processing of VEGF-R2 by ␥-secretase. ␥-Secretase generates the amyloid-␤ (A␤) peptide of Alzheimer disease from its precursor (amyloid precursor protein). This peptide is also a component of drusen in dry AMD. The results support the hypothesis that misregulation of ␥-secretase may not only lead to A␤ deposits in dry AMD but can also be damaging to RPE function by blocking the protective effects of PEDF to prevent VEGF from driving the dry to wet AMD transition. Age-related macular degeneration (AMD)2 is often diagnosed by the appearance of subretinal fluid. This fluid causes a local detachment of the retina in the macular area resulting in decreased visual acuity in the center of the visual field (1). The resulting macular edema can lead to complete vision loss (2). Although the excessive fluid mainly comes from capillaries in the inner retina, the removal of subretinal fluid is dependent on the RPE. The maintenance of RPE barrier function is essential for the efficient removal of the fluid (3), and the disruption of the RPE barrier can eventually lead to choroidal neovascularization.Recent clinical studies have shown that intravitreally administered anti-VEGF compounds are effective therapies for choroidal neovascularization (4 -6). Originally, VEGF was described as an endothelial angiogenic and vasopermeability factor. The leakage through the vessels of the inner retina increases in response to VEGF (7,8). However, the release of VEGF also affects RPE function (9 -11). We have recently shown that RPE barrier integrity is modulated by VEGF through apically oriented VEGF-R2 receptors (12). Thus, there is a growing body of evidence that intraocular VEGF can increase the permeability of both the inner and outer bloodretina barriers, contributing to the accumulation of subretinal fluid and macular ed...

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Section: Discussionsupporting

confidence: 93%

Pigment Epithelium-derived Factor Maintains Retinal Pigment Epithelium Function by Inhibiting Vascular Endothelial Growth Factor-R2 Signaling through γ-Secretase

Ablonczy

Prakasam

Fant

et al. 2009

Journal of Biological Chemistry

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“…IBM remains the only known condition in which A␤ accumulates pathologically outside the central nervous system, except for age-related macular degeneration. 11 This distinction implicates a critical role for A␤ in the pathogenesis of IBM. A noteworthy difference between two degenerative processes is the location in which A␤ accumulates.…”

mentioning

confidence: 99%

Genetically Augmenting Aβ42 Levels in Skeletal Muscle Exacerbates Inclusion Body Myositis-Like Pathology and Motor Deficits in Transgenic Mice

Kitazawa

Green

Caccamo

et al. 2006

The American Journal of Pathology

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The pathogenic basis of inclusion body myositis (IBM), the leading muscle degenerative disease afflicting the elderly, is unknown, although the histopathological features are remarkably similar to those observed in Alzheimer's disease. One leading hypothesis is that the buildup of amyloid-␤ (A␤) peptide within selective skeletal muscle fibers contributes to the degenerative phenotype. A␤ is a small peptide derived via endoproteolysis of the amyloid precursor protein (APP). To determine the pathogenic effect of augmenting A␤42 levels in skeletal muscle, we used a genetic approach to replace the endogenous wildtype presenilin-1 (PS1) allele with the PS1 M146V allele in MCK-APP mice. Although APP transgene expression was unaltered, A␤ levels, particularly A␤42, were elevated in skeletal muscle of the double transgenic (MCK-APP/PS1) mice compared to the parental MCK-APP line. Elevated phospho-tau accumulation was found in the MCK-APP/PS1 mice, and the greater activation of GSK-3␤ and cdk5 were observed. Other IBM-like pathological features, such as inclusion bodies and inflammatory infiltrates, were more severe and prominent in the MCK-APP/PS1 mice. Motor coordination and balance were more adversely affected and manifested at an earlier age in the MCK-APP/PS1 mice. The data presented here provide experimental evidence that A␤42 plays a proximal and critical role in the muscle degenerative process. Inclusion body myositis (IBM), the most prevalent muscle disorder among the elderly, is characterized by proximal and distal skeletal muscle weakness.1-3 The clinical features of this disorder are characterized by muscle weakness and atrophy, with selective involvement of both proximal and distal muscle groups, including the quadriceps, iliopsoas, triceps, and biceps muscles. In sporadic IBM, the majority of patients usually exhibit proximal weakness, and the quadriceps are more severely affected compared to other lower limb muscles.3 In hereditary IBM, however, affected muscles may exhibit a more restricted focus. For example, the quadriceps may be selectively spared in certain autosomal recessive cases. 4,5 Histopathologically, both sporadic and hereditary IBM are characterized by atrophic muscle fibers and fibers containing rimmed vacuoles and abnormal protein aggregates, particularly amyloid-␤ (A␤), which is derived via endoproteolysis of the amyloid precursor protein (APP), and hyperphosphorylated tau. 2,6 -10 IBM and Alzheimer's disease (AD) share many pathohistological features including the buildup of aggregated proteins such as A␤ and tau. In this regard, IBM can also be considered as a proteinopathy. As in AD, the role of the A␤ peptide is unresolved, although evidence suggests that it plays an early and critical role in the muscle degeneration. IBM remains the only known condition in which A␤ accumulates pathologically outside the central nervous system, except for age-related macular degeneration.11 This distinction implicates a critical role for A␤ in the pathogenesis of IBM. A noteworthy difference between...

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“…On the one hand, numerous publications connect the pathogenesis of AD with age-related macular degeneration (ARMD). [43][44] ARMD is a disease that produces a slow and progressive macular atrophy that finally leads to a degeneration of visual acuity. Therefore, according to the current bibliography, it is difficult to determine what the main cause of the reduction is in macular thickness, ARMD or AD.…”

Section: Discussionmentioning

confidence: 99%

Macular Thickness in Subjective Memory Complaints and Mild Cognitive Impairment: A Non-Invasive Biomarker

Castejón

Dudekova

Gallego

et al. 2016

Neuro-Ophthalmology

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Alzheimer's disease (AD) is the main cause of dementia worldwide, which implies an important socioeconomic problem in developed countries. Efforts to find biomarkers to diagnose AD have been intensified, especially, to detect cognitive impairment in its early stages, also known as mild cognitive impairment (MCI). Besides, there are individuals referring memory loss that is unnoticeable in the family environment and presenting normal neuropsychological tests. The former patients are included in a clinical picture that has been recently called subjective memory complaints (SMC). To achieve an early diagnosis, optical coherence tomography (OCT) has been used to measure macular thickness in patients diagnosed with MCI (supported by neuropsychological tests) and SMC (not based on neuropsychological battery). Statistically significant differences have been found in the macular thickness of the control group (274.96 ± 17.61 µm) and for both MCI (259.48 ± 22.39 µm) and SMC (261.45 ± 24.26 µm) patients. In the near future, OCT could become a reliable biomarker and a useful tool for AD screening as well as for the monitoring of the cognitive impairment associated with AD. ARTICLE HISTORY

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The potential role of amyloid in the pathogenesis of age-related macular degeneration

Cited by 195 publications

References 62 publications

Pigment Epithelium-derived Factor Maintains Retinal Pigment Epithelium Function by Inhibiting Vascular Endothelial Growth Factor-R2 Signaling through γ-Secretase

Pigment Epithelium-derived Factor Maintains Retinal Pigment Epithelium Function by Inhibiting Vascular Endothelial Growth Factor-R2 Signaling through γ-Secretase

Genetically Augmenting Aβ42 Levels in Skeletal Muscle Exacerbates Inclusion Body Myositis-Like Pathology and Motor Deficits in Transgenic Mice

Macular Thickness in Subjective Memory Complaints and Mild Cognitive Impairment: A Non-Invasive Biomarker

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