Amyloid β Induces Early Changes in the Ribosomal Machinery, Cytoskeletal Organization and Oxidative Phosphorylation in Retinal Photoreceptor Cells

Abstract

Amyloid β (Aβ) accumulation and its aggregation is characteristic molecular feature of the development of Alzheimer’s disease (AD). More recently, Aβ has been suggested to be associated with retinal pathology associated with AD, glaucoma and drusen deposits in age related macular degeneration (AMD). In this study, we investigated the proteins and biochemical networks that are affected by Aβ in the 661 W photoreceptor cells in culture. Time and dose dependent effects of Aβ on the photoreceptor cells were determined utilizing tandem mass tag (TMT) labeling-based quantitative mass-spectrometric approach. Bioinformatic analysis of the data revealed concentration and time dependent effects of the Aβ peptide stimulation on various key biochemical pathways that might be involved in mediating the toxicity effects of the peptide. We identified increased Tau phosphorylation, GSK3β dysregulation and reduced cell viability in cells treated with Aβ in a dose and time dependent manner. This study has delineated for the first-time molecular networks in photoreceptor cells that are impacted early upon Aβ treatment and contrasted the findings with a longer-term treatment effect. Proteins associated with ribosomal machinery homeostasis, mitochondrial function and cytoskeletal organization were affected in the initial stages of Aβ exposure, which may provide key insights into AD effects on the photoreceptors and specific molecular changes induced by Aβ peptide.

Prodromal Alzheimer’s Disease: Constitutive Upregulation of Neuroglobin Prevents the Initiation of Alzheimer’s Pathology

“…Thus, Aβ, perhaps via oxidative stress (but not only), would affect microtubule organization and dynamics and consequently neuronal architecture. In support of this possibility, recent works have shown that changes in microtubules and dendritic simplification are among the earliest manifestation of Aβ toxicity ( Wu et al, 2010 ; Deng et al, 2019 ). More importantly, dendritic tree simplification is a typical feature of early AD, both in vivo in animal models of the disease and in the human brain ( Golovyashkina et al, 2015 ).…”

Role of Retinal Amyloid-β in Neurodegenerative Diseases: Overlapping Mechanisms and Emerging Clinical Applications

“…Using a familial AD mice model to study AMD pathology, Aβ accumulations in sub-RPE drusen were observed with early PRC functional deficiencies without PRC cell loss, indicating that Aβ pathology may lead to RPE dysfunction that disrupts its neuroprotective effect for the PRC [ 91 ]. Aβ-treated PRC cell lines also showed a dose-response decrease in PRC viability, indicating a direct effect on visual sensitivity in AMD [ 110 ]. Since retinal Aβ accumulations in AMD associated drusen prior to neurodegeneration of the PRC, it supports the use of preventative strategies like the use of nutritional supplements and maintaining a healthy diet in early AD [ 111 ].…”

ROS production and mitochondrial dysfunction driven by PU.1-regulated NOX4-p22phox activation in Aβ-induced retinal pigment epithelial cell injury

“…We identified 10660 and 4243 nonredundant peptides and proteins, respectively. It has previously been shown that Aβ can trigger a reorganization of the cytoskeletal network 30 . In this study, we examined the regulatory mechanisms downstream of Aβ 1-40 and found cytoskeleton-related proteins to be the most abundant by MS analysis.…”