gms | German Medical Science

Alzheimer’s disease (AD) is characterized histopathologically by extracellular amyloid-β (Aβ) plaques and neurofibrillary tangles composed of abnormal tau protein. Besides these hallmarks certain reactive and inflammatory processes including the activation of the innate immune response are also evident.

The endoplasmic reticulum (ER) protein SigR1 has diverse cellular functions which include chaperone activities and the regulation of calcium signalling, synaptic transmission and inflammatory processes. Drugs targeting SigR1 have been shown to be neuroprotective in several disease models including SOD1 mice, a model for Amyotrophic lateral sclerosis (ALS). Recent reports also suggested a significant role of SigR1 in AD pathogenesis. In the present study we focused on the role of in AD pathology. We studied AD patient brain tissue, a transgenic AD mouse model and a cell culture model treated with pathogenic Aβ peptide. We found that SigR1 protein is abnormally modified in the brains of AD patients and mice and that neurotoxicity induced by Aβ involves altered ER structure and function. These findings support the notion that modification of SigR1 might be a therapeutic target in AD.

Note: J. Weis & A. Goswami contributed equally to this work.