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A. B. Savoia, D. Aggarwal, F. N. Ross-Cisneros, A. A. Sadun; Immunohistochemical Study of High Mobility Group Box 1 in Alzheimer’s Disease Optic Nerves. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5351.
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To investigate the presence of High Mobility Group Box 1 (HMGB1) in Alzheimer’s disease (AD) optic nerves. HMGB1 is a non-histone DNA binding protein which can translocate from the nucleus to the cytoplasm during states of cellular stress or damage. It can then act as both a cytokine and ligand stimulating the receptor for advanced glycation end products (RAGE) when released extracellularly resulting in inflammation and tissue damage.
Optic nerve specimens were obtained at autopsy from twelve patients with AD and compared to six normal age-matched control tissues. AD tissues were supplied by our Alzheimer’s Disease Research Center (ADRC) and controls were purchased through local eye banks. Tissues were immersion fixed in neutral buffered formalin, dissected into cross-sectional profiles just proximal to the globe, then processed and embedded into paraffin blocks. Sections were cut at 5 µm and immunostained, using an indirect method with horseradish peroxidase and diaminobenzidine as the substrate-chromogen, with a rabbit anti-human HMGB1 polyclonal antibody at a dilution of 1:1,000. Light microscopic images were viewed on a Zeiss Axioskop microscope and captured by a digital camera and saved to a computer.
Control optic nerves immunostained for HMGB1 demonstrated very specific nuclear but not cytoplasmic staining in most cells. AD tissues revealed both nuclear and cytoplasmic localization of the chromogen. The cytoplasmic staining was usually intense and highlighted this region’s entire area. It was also observed that the cell cytoplasm appeared vacuolated with an empty space often circumscribing the entire, though intact, nucleus. Glial cells appeared to be the primary target of the immunostaining with astrocytes being the most common glial cell labeled.
HMGB1 is a non-histone DNA binding protein that can act as a ligand to RAGE which can initiate pro-inflammatory pathways. Increased presence of HMGB1 in cytoplasm of glial cells in AD optic nerves may indicate that HMGB1, when released extracellularly, may bind to RAGE thus mediating inflammatory pathways. Hence, HMGB1 may play a role in the pathogenesis of optic neuropathy as observed in a subpopulation of Alzheimer’s disease patients.
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