ABSTRACT
Myeloperoxidase (MPO) is a myeloid-specific enzyme that generates beneficial microbicidal oxidants, but the human MPO (hMPO) gene can escape this restriction in neurotoxic situations, enabling expression in neurons, astrocytes, or microglia in Alzheimer's disease (AD), Parkinson's disease (PD), or multiple sclerosis (MS). To investigate the impact of MPO expression in these neurodegenerative diseases, a humanized MPO mouse model was created. When crossed to mouse models of AD or PD, the hMPO transgene was expressed robustly in subsets of astrocytes, neurons, or microglia, and this resulted in increased lipid peroxidation, carbamylation, chlorination, and nitration, leading to greater memory impairment in an AD model and greater motor impairment in a PD model. This atypical expression of hMPO involves an upstream Alu element encoding binding sites for SP1 and nuclear receptors. A polymorphism in this Alu, −463G, increases hMPO expression and has been linked to risk for AD, cardiovascular disease, and epithelial cancers. This chapter discusses the evidence of aberrant MPO expression in AD, PD, and MS and the associated oxidative damage resulting in memory or motor impairment through analysis of postmortem human brain and mouse disease models expressing the human MPO gene. These findings raise the possibility that MPO inhibitors could slow the progression of AD, PD, or MS.
