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M. Y. Wang, F. N. Ross-Cisneros, A. A. Sadun; Immunohistochemical Study of the Receptor for Advanced Glycation End Products in the Microvasculature of Alzheimer’s Optic Nerves. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5345.
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Several studies have suggested that the receptor for advanced glycation end products (RAGE) are up-regulated in the microvasculature of Alzheimer’s disease (AD) to actively mediate the transport of β-amyloid across the blood-brain barrier into the brain from the systemic circulation. Once bound, the interaction of β-amyloid and RAGE could lead to a chronic inflammatory state amplified and perpetuated by the RAGE axis. The goal of this study is to determine whether there is any increase in the expression of RAGE in the microvasculature of the Alzheimer’s optic nerves.
We looked at 10 retrobulbar optic nerves (1-3 mm from the globe) from donors previously diagnosed with AD. These were compared to 5 age-matched control optic nerves from individuals with no AD. All tissues were formalin-fixed and embedded in paraffin. Tissue sections were cut at 5 µm and immunostained with antibodies directed against human RAGE and endothelia (CD-31) both individually (immunoperoxidase) and for colocalization of these antigens (immunofluorescence) within optic nerve microvasculature. Tissue sections were observed on a standard bright field (immunoperoxidase) and confocal (immunofluorescence) microscope . The intensity and localization of immunolabeling for RAGE was qualitatively graded on a scale from 0 to 3. Grade 0 was defined as no staining, Grade 1 as mild staining, Grade 2 as moderate staining, and Grade 3 as strong staining.
Immunoreactivity for RAGE and endothelia were well defined. The immnolabelling for RAGE appeared "punctate" and the label for endothelia (CD-31) outlined their course within optic nerve connective tissue and fiber bundle parenchyma. In AD optic nerves, there was moderate to strong staining (Grade 2 and 3) for RAGE within the microvasculature, frequently outlining the blood vessels. In contrast, the staining for RAGE was largely minimal (Grade 1-2) in the microvasculature of control nerves. RAGE appeared to increase with age in both groups.
Our observations suggest that AD is associated with an increase in RAGE within the microvasculature of the optic nerve. RAGE is a multi-ligand receptor that can bind to β-amyloid and other pro-inflammatory ligands. We postulate that the increase in RAGE within the microvasculature of AD optic nerve may contribute to the pathogenetic processes of optic neuropathy observed in a subpopulation of these patients.
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