Beta-Amyloid Precursor Protein (βAPP) Processing in Alzheimer’s Disease (AD) and Age-Related Macular Degeneration (AMD)

Zhao, Yuhai; Bhattacharjee, Surjyadipta; Jones, Brandon M.; Hill, James M.; Clément, Christian; Sambamurti, Kumar; Dua, Prerna; Lukiw, Walter J.

doi:10.1007/s12035-014-8886-3

Cited by 61 publications

(73 citation statements)

References 105 publications

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“…This combination of genetic and environmental stressors is a feature shared with several other neurodegenerative diseases, including Alzheimer and Huntington diseases. [49][50][51] Along with AMD, these diseases are characterized by the accumulation of deposits, for example amyloid deposits in Alzheimer disease, and drusen (chemically complex deposits that form under the RPE) in AMD. In neurodegenerations, autophagy deficiency has been implicated in the inadequate cellular response to the various disease-causing factors.…”

Section: Discussionmentioning

confidence: 99%

Deletion of autophagy inducerRB1CC1results in degeneration of the retinal pigment epithelium

et al. 2015

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Autophagy regulates cellular homeostasis and response to environmental stress. Within the retinal pigment epithelium (RPE) of the eye, the level of autophagy can change with both age and disease. The purpose of this study is to determine the relationship between reduced autophagy and age-related degeneration of the RPE. The gene encoding RB1CC1/FIP200 (RB1-inducible coiled-coil 1), a protein essential for induction of autophagy, was selectively knocked out in the RPE by crossing Best1-Cre mice with mice in which the Rb1cc1 gene was flanked with Lox-P sites (Rb1cc1(flox/flox)). Ex vivo and in vivo analyses, including western blot, immunohistochemistry, transmission electron microscopy, fundus photography, optical coherence tomography, fluorescein angiography, and electroretinography were performed to assess the structure and function of the retina as a function of age. Deletion of Rb1cc1 resulted in multiple autophagy defects within the RPE including decreased conversion of LC3-I to LC3-II, accumulation of autophagy-targeted precursors, and increased numbers of mitochondria. Age-dependent degeneration of the RPE occurred, with formation of atrophic patches, subretinal migration of activated microglial cells, subRPE deposition of inflammatory and oxidatively damaged proteins, subretinal drusenoid deposits, and occasional foci of choroidal neovascularization. There was secondary loss of photoreceptors overlying the degenerated RPE and reduction in the electroretinogram. These observations are consistent with a critical role of autophagy in the maintenance of normal homeostasis in the aging RPE, and indicate that disruption of autophagy leads to retinal phenotypes associated with age-related degeneration.

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Section: Discussionmentioning

confidence: 99%

Deletion of autophagy inducerRB1CC1results in degeneration of the retinal pigment epithelium

et al. 2015

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“…Extracellular amyloid beta (Aβ) deposition, oxidative stress, and inflammation have all been implicated in both AD and AMD 14, 19, 20 . Although, the biological function of Aβ is not yet fully understood it is thought to have a role in synaptic physiology 21–23 .…”

Section: Introductionmentioning

confidence: 99%

Amyloid β peptides overexpression in retinal pigment epithelial cells via AAV-mediated gene transfer mimics AMD-like pathology in mice

Prasad

Zhu

Verma

et al. 2017

Sci Rep

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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.Age-related macular degeneration (AMD) is a late-onset, progressive retinal neurodegenerative disease and the leading cause of severe and irreversible vision loss in the elderly in developed countries [1][2][3][4][5] . This disease primarily affects the macular region of human retina, which is crucial for central vision and perception of finer details, resulting in a progressive loss of high-resolution central vision in people afflicted with this disorder. The visual impairment associated with AMD occurs as a consequence of two different forms of the disease-dry AMD (geographical atrophy or nonexudative AMD), which is characterized by progressive retinal degeneration involving the photoreceptors and the retinal pigment epithelial (RPE) cells, or the more severe form-wet AMD (choroidal neovascularization or exudative AMD), which is characterized by the growth of new blood vessels from the choroid into the neural retina causing photoreceptor degeneration 2,6,7 . While wet AMD can be treated by laser photocoagulation, photodynamic therapy and intravitreal injections of anti-vascular endothelial growth factor (VEGF)-A and other angiogenic inhibitors, there is no effective treatment available currently for dry AMD 5,[8][9][10] . AMD is clinically characterized by the presence of extracellular deposits known as drusen located between the retinal pigment epithelium (RPE) and Bruch's membrane (sub-RPE) in the macular region. Drusens are also observed in the normal aging eye, however the presence of large drusens in high numbers in the macular region has been identifi...

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“…Currently we cannot fully explain the mechanisms underlying Ab accumulation in the eye and higher visual centres hindering development of possible therapeutic options. Further investigations into retinal Ab accumulation may be potentially insightful in terms of understanding neurodegenerative mechanisms as Ab peptides have established neurotoxic properties and play a major role in inducing pathological changes in the AD brain [9,10]. Several studies highlight the association of AD with inner retinal and ON degenerative changes which is reminiscent of glaucoma pathology.…”

Section: Introductionmentioning

confidence: 99%

One protein, multiple pathologies: multifaceted involvement of amyloid β in neurodegenerative disorders of the brain and retina

Gupta

Chitranshi

et al. 2016

Cell. Mol. Life Sci.

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Accumulation of amyloid β (Aβ) and its aggregates in the ageing central nervous system is regarded synonymous to Alzheimer's disease (AD) pathology. Despite unquestionable advances in mechanistic and diagnostic aspects of the disease understanding, the primary cause of Aβ accumulation as well as its in vivo roles remains elusive; nonetheless, the majority of the efforts to address pathological mechanisms for therapeutic development are focused towards moderating Aβ accumulation in the brain. More recently, Aβ deposition has been identified in the eye and is linked with distinct age-related diseases including age-related macular degeneration, glaucoma as well as AD. Awareness of the Aβ accumulation in these markedly different degenerative disorders has led to an increasing body of work exploring overlapping mechanisms, a prospective biomarker role for Aβ and the potential to use retina as a model for brain related neurodegenerative disorders. Here, we present an integrated view of current understanding of the retinal Aβ deposition discussing the accumulation mechanisms, anticipated impacts and outlining ameliorative approaches that can be extrapolated to the retina for potential therapeutic benefits. Further longitudinal investigations in humans and animal models will determine retinal Aβ association as a potential pathognomonic, diagnostic or prognostic biomarker.

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Beta-Amyloid Precursor Protein (βAPP) Processing in Alzheimer’s Disease (AD) and Age-Related Macular Degeneration (AMD)

Cited by 61 publications

References 105 publications

Deletion of autophagy inducerRB1CC1results in degeneration of the retinal pigment epithelium

Deletion of autophagy inducerRB1CC1results in degeneration of the retinal pigment epithelium

Amyloid β peptides overexpression in retinal pigment epithelial cells via AAV-mediated gene transfer mimics AMD-like pathology in mice

One protein, multiple pathologies: multifaceted involvement of amyloid β in neurodegenerative disorders of the brain and retina

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