Obesity and low testosterone interact to increase vulnerability to Alzheimer's disease pathogenesis

Abstract

a possible role for c2orf40, an orphan gene that encodes Ecrg4, a 17,000 Dalton, secreted protein that has been previously associated with neural progenitor responsiveness after CNS injury, microglial activation in CNS tumors, and white matter senescence. Methods: Adult human cerebral cortical and choroid plexus tissue samples were obtained at autopsy. Ecrg4 gene expression in Alzheimer’s disease patients, cognitively normal, and disease age-matched controls was studied by quantitative RT PCR using the standard curve method. Processed protein forms were determined by Western blotting, and their distribution was examined in tissue sections using standard immunohistochemical staining techniques. Results: RT-qPCR demonstrated increased cerebral cortical Ecrg4 gene expression in AD, whereas similar analyses performed on frozen samples of choroid plexus showed no significant differences between AD and control. The peptide form of Ecrg4 detected in cortical gray matter of AD patients was a processed carboxy-terminal fragment of 8-10 kDa that was previously shown to interact with the innate immunity receptor complex. Immunocytochemical studies showed increased staining intensity in microglial cells and in intravascular blood-borne monocytes present within the cerebral cortical white matter of AD patients. Staining intensity appeared to be slightly diminished within cortical gray matter, except for prominent staining in rare neurofibrillary tangles. The staining pattern of the choroid plexus was similar in AD patients and controls, with robust immunoreactivity noted along the apical border of epithelial cells. Conclusions: Growing evidence suggests a role for Ecrg4 as an inflammatory mediator in microglial activation and as an initiator of oligodendrocyte precursor senescence. These data are the first to describe c2orf40 in the brain of Alzheimer’s disease patients and suggest that the Ecrg4 it encodes may participate in the activation and recruitment of microglial cells in cerebral white matter neuroinflammation.