Peptidyl arginine deiminases (PADs) catalyze a post-translational protein 
modification reaction called citrullination, where arginine is converted to 
citrulline. This modification has been linked to the pathogenesis of autoimmune 
diseases including rheumatoid arthritis (RA). More recently, several studies 
have suggested that Alzheimer's disease (AD), a devastating neurodegenerative 
disorder, may have an autoimmune component. In the present study, we have 
investigated the possibility that expression of PADs and protein citrullination 
plays a role in the production of brain-reactive autoantibodies that may 
contribute to Alzheimer's-related brain pathology. Here, we report the selective 
expression of the PAD isoforms, PAD2 and PAD4, in astrocytes and neurons, 
respectively, and the concomitant accumulation of citrullinated proteins within 
PAD4-expressing cells, including neurons of the hippocampus and cerebral cortex. 
Expression of PADs and citrullinated proteins is prominent in brain regions 
engaged in neurodegenerative changes typical for AD pathology. Furthermore, we 
also demonstrate that the pentatricopeptide repeat domain2 (PTCD2) protein, an 
antigen target of a prominent AD diagnostic autoantibody, is present in a 
citrullinated form in AD brains. Our results suggest that disease-associated 
neuronal loss results in the release of cellular contents, including 
citrullinated proteins, into the brain interstitium. We propose that these 
citrullinated proteins and their degradation fragments enter into the blood and 
lymphatic circulation, and some are capable of eliciting an immune response that 
results in the production of autoantibodies. The long-term and progressive 
nature of AD and other neurodegenerative diseases results in chronic exposure of 
the immune system to these citrullinated products and may drive the continual 
production of autoantibodies.