Apolipoprotein E2 and E3, but Not E4, Promote Retinal Pathologic Neovascularization

Masuda, Tomomi; Shimazawa, Masamitsu; Hashimoto, Yuichi; Kojima, Atsushi; Nakamura, Shinsuke; Suemori, Shinsuke; Mochizuki, Kiyofumi; Kawakami, Hideaki; Kawase, Kazuhide; Hara, Hideaki

doi:10.1167/iovs.16-20539

Cited by 20 publications

(13 citation statements)

References 62 publications

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“…Moreover, the harmful effect of APOE 4 has been associated not only to a higher risk of AD but also to a higher risk or different clinical outcomes for other neurological [195–198] and non-neurological conditions [199–203]. These latter findings support the hypothesis that APOE is very much indeed a possible general modifier of various biological and consequently, clinical phenomena.…”

Section: Apoe Polymorphism In Normal and Pathologic Conditions Of Thementioning

confidence: 57%

Impact of Apolipoprotein E gene polymorphism during normal and pathological conditions of the brain across the lifespan

Iacono

Feltis

2019

Aging

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The central nervous system (CNS) is the cellular substrate for the integration of complex, dynamic, constant, and simultaneous interactions among endogenous and exogenous stimuli across the entire human lifespan. Numerous studies on aging-related brain diseases show that some genes identified as risk factors for some of the most common neurodegenerative diseases - such as the allele 4 of APOE gene (APOE4) for Alzheimer’s disease (AD) - have a much earlier neuro-anatomical and neuro-physiological impact. The impact of APOE polymorphism appears in fact to start as early as youth and early-adult life. Intriguingly, though, those same genes associated with aging-related brain diseases seem to influence different aspects of the brain functioning much earlier actually, that is, even from the neonatal periods and earlier. The APOE4, an allele classically associated with later-life neurodegenerative disorders as AD, seems in fact to exert a series of very early effects on phenomena of neuroplasticity and synaptogenesis that begin from the earliest periods of life such as the fetal ones.We reviewed some of the findings supporting the hypothesis that APOE polymorphism is an early modifier of various neurobiological aspects across the entire human lifespan - from the in-utero to the centenarian life - during both normal and pathological conditions of the brain.

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Section: Apoe Polymorphism In Normal and Pathologic Conditions Of Thementioning

confidence: 57%

Impact of Apolipoprotein E gene polymorphism during normal and pathological conditions of the brain across the lifespan

Iacono

Feltis

2019

Aging

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“…This determined that ApoE4 has transitory synaptic and vascular effects during retinal development, before and after the neonatal period, respectively. Moreover, VEGF in aged retina has proangiogenic effects that promote macular edema, diabetic retinopathy, and macular holes [ 89 , 90 ].…”

Section: Pathological Mechanisms Of a β And Taumentioning

confidence: 99%

“…ApoE can be expressed in RPE, GCL, and BM and is synthesized in Müller cells [ 89 ]. ApoE is involved in uptake, processing, transport, and clearance of lipids for retinal metabolism; therefore, disturbance of this process may lead to cholesterol and lipid accumulation in BM [ 43 ].…”

Section: Pathological Mechanisms Of a β And Taumentioning

confidence: 99%

“…Distinct to AD, ApoE4 confers protection against AMD because it improves BM permeability, facilitates lipid transportation, and consequently leads to reduced debris accumulation in drusen formation. In contrast, ApoE2 increases the risk of AMD apparition because it induces VEGF as a proangiogenic agent [ 43 , 89 , 91 , 92 ]. Contradictorily, some studies have shown increased AMD in AD patients [ 93 ], while others show no association [ 94 ].…”

Section: Pathological Mechanisms Of a β And Taumentioning

confidence: 99%

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Visual Features in Alzheimer’s Disease: From Basic Mechanisms to Clinical Overview

et al. 2018

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Alzheimer's disease (AD) is the leading cause of dementia worldwide. It compromises patients' daily activities owing to progressive cognitive deterioration, which has elevated direct and indirect costs. Although AD has several risk factors, aging is considered the most important. Unfortunately, clinical diagnosis is usually performed at an advanced disease stage when dementia is established, making implementation of successful therapeutic interventions difficult. Current biomarkers tend to be expensive, insufficient, or invasive, raising the need for novel, improved tools aimed at early disease detection. AD is characterized by brain atrophy due to neuronal and synaptic loss, extracellular amyloid plaques composed of amyloid-beta peptide (Aβ), and neurofibrillary tangles of hyperphosphorylated tau protein. The visual system and central nervous system share many functional components. Thus, it is plausible that damage induced by Aβ, tau, and neuroinflammation may be observed in visual components such as the retina, even at an early disease stage. This underscores the importance of implementing ophthalmological examinations, less invasive and expensive than other biomarkers, as useful measures to assess disease progression and severity in individuals with or at risk of AD. Here, we review functional and morphological changes of the retina and visual pathway in AD from pathophysiological and clinical perspectives.

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“…Animal and cellular model studies revealed that APOE4 is associated with impaired cellular plasticity [32, 34, 35]. It is thus likely that the negative effects of APOE4 in AD are due to this impaired neuronal synaptic plasticity, whereas in AMD, in which the key pathology is increased angiogenesis and vascular plasticity, the effects of apoE4 could be protective due to the reduction in retinal pathological neovascularization [36].…”

Section: Introductionmentioning

confidence: 99%

ApoE4: an emerging therapeutic target for Alzheimer’s disease

Safieh

Korczyn

Michaelson

2019

BMC Med

343

245

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BackgroundThe growing body of evidence indicating the heterogeneity of Alzheimer’s disease (AD), coupled with disappointing clinical studies directed at a fit-for-all therapy, suggest that the development of a single magic cure suitable for all cases may not be possible. This calls for a shift in paradigm where targeted treatment is developed for specific AD subpopulations that share distinct genetic or pathological properties. Apolipoprotein E4 (apoE4), the most prevalent genetic risk factor of AD, is expressed in more than half of AD patients and is thus an important possible AD therapeutic target.ReviewThis review focuses initially on the pathological effects of apoE4 in AD, as well as on the corresponding cellular and animal models and the suggested cellular and molecular mechanisms which mediate them. The second part of the review focuses on recent apoE4-targeted (from the APOE gene to the apoE protein and its interactors) therapeutic approaches that have been developed in animal models and are ready to be translated to human. Further, the issue of whether the pathological effects of apoE4 are due to loss of protective function or due to gain of toxic function is discussed herein. It is possible that both mechanisms coexist, with certain constituents of the apoE4 molecule and/or its downstream signaling mediating a toxic effect, while others are associated with a loss of protective function.ConclusionApoE4 is a promising AD therapeutic target that remains understudied. Recent studies are now paving the way for effective apoE4-directed AD treatment approaches.

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Apolipoprotein E2 and E3, but Not E4, Promote Retinal Pathologic Neovascularization

Abstract: These results demonstrate that ApoE2 and ApoE3, but not ApoE4, have proangiogenic effects, and the increased expression of ApoE in the vitreous humor of patients with PDR and DME indicates that ApoE2 and ApoE3 are involved in the development of retinal neovascularization in eyes.

Cited by 20 publications

References 62 publications

Impact of Apolipoprotein E gene polymorphism during normal and pathological conditions of the brain across the lifespan

Impact of Apolipoprotein E gene polymorphism during normal and pathological conditions of the brain across the lifespan

Visual Features in Alzheimer’s Disease: From Basic Mechanisms to Clinical Overview

ApoE4: an emerging therapeutic target for Alzheimer’s disease

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