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W. J. Lukiw, P. K. Mukherjee, J. G. Cui, N. G. Bazan; Down-Regulation of Sortilin-1 (SORL1) and Increased Amyloid Beta (Aβ) Abundance Characterize Stressed Retinal Pigment Epithelial (ARPE-19) Cells and Age-Related Macular Degeneration (AMD). Invest. Ophthalmol. Vis. Sci. 2009;50(13):2339.
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Progressive and debilitating retinal diseases such as age-related macular degeneration (AMD) are leading causes of central visual impairment in Westernized societies. The pathogenic mechanisms contributing to AMD onset and progression are not well understood. The purpose of these experiments was to unravel the molecular-genetic, inflammatory and degenerative mechanisms of AMD using stressed ARPE-19 cell models and AMD affected human retinal tissues.
Post-mortem human retinal RNA analysis; ARPE-19 cell culture; cytokine- (TNF) and hydrogen peroxide- (H2O2) induced oxidative stress; DNA array (Affymetrix, Santa Clara, CA); Northern analysis; RT-PCR; Western analysis; statistical analysis; bioinformatics (Silicon Genetics, Redwood City, CA).
Compared to age-matched controls, post-mortem AMD retina and cytokine- and peroxide-stressed ARPE-19 cells exhibited down-regulation of SORL1 (LR11), a key modulator of beta-amyloid precursor protein (βAPP) trafficking, and increases in a tandem beta- and gamma-secretase-generated neurotoxic fragment of βAPP known as the self-aggregating and pro-inflammatory Aβ42 peptide. A soluble, neurotrophic, neuritogenic 612 amino acid βAPP fragment known as sAPP was found to be reduced in abundance. The beta- and gamma-secretase-mediated mechanism for up-regulation of Aβ42 peptide in AMD and in AMD models is currently under investigation.
Biological systems that support and degrade the membrane-spanning polytopic βAPP holoprotein are abundantly present in both ARPE-19 cells and in human retina. Cytokine- and oxidation-induced stress activates pathogenic βAPP processing and trafficking. Both apolipoprotein E (ApoE) speciation and SORL1 (LR11), a neuronal-enriched sorting protein of the ApoE receptor family, are known membrane-bound contributors to differential βAPP processing pathways in progressive neurodegenerative disease. βAPP depletion, increases in the abundance of βAPP’s catabolic metabolites such as Aβ42 peptide, coupled to deficiencies in SORL1 (LR11) may function to propagate pathogenic signaling events that support inflammatory and degenerative aspects of AMD. Pharmacotherapeutic strategies targeted at lowering Aβ42 peptide abundance and neutralizing Aβ42’s pathogenic effects in neurodegenerative disease may also be useful in the clinical treatment of AMD.
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