Abstract
Myeloperoxidase (MPO) is an enzyme expressed mostly by neutrophils and is a primary mediator of neutrophils oxidative stress response. While a profound body of evidence associates neutrophil-derived MPO in the pathogenesis of Alzheimer’s disease (AD), this role has not been assessed in an animal model of AD. Here, we produced hematologic chimerism in the 5XFAD mouse model of AD, with MPO deficient mice, resulting in 5XFAD with hematologic MPO deficiency (5XFAD-MPO KO). Behavioral examinations of 5XFAD-MPO KO showed significant superior performance in spatial learning and memory, associative learning, and anxiety/risk assessment behavior, as compared to 5XFAD mice transplanted with WT cells (5XFAD-WT). Hippocampal immunohistochemical and mRNA expression analyses showed significantly reduced levels of inflammatory mediators in 5XFAD-MPO KO mice with no apparent differences in the numbers of amyloid-β plaques. In addition, immunoblotting and mRNA analyses showed significantly reduced levels of APOE in 5XFAD-MPO KO. Together, these results indicate a substantial involvement of neutrophil-derived MPO in the pathology of 5XFAD model of AD and suggest MPO as a potential therapeutic target in AD.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disease and the major cause of dementia in the elderly
We subjected 2-month old mice to hematopoietic ablation by exposure to myeloablative irradiation, followed by re-population with bone marrow (BM) cells derived from either MPO-KO or WT C57BL/6 mice. This resulted in four experimental groups; (1) WT with WT BM (WT-WT), (2) WT with MPO-KO BM (WT-MPO KO), (3) 5XFAD mice with WT BM (5XAD-WT), and (4) 5XAD with MPO-KO BM (5XFAD-MPO KO) (Figure 1A)
Blood peroxidase activity 2 months following transplantation revealed a substantial reduction in the percentage of cells with peroxidase activity following MPO-KO BM transplantation (Figure 1B)
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disease and the major cause of dementia in the elderly It is characterized by a progressive cognitive decline along with multiple neuropathological features such as extracellular accumulation of amyloid-β plaques, intraneuronal accumulation of hyperphosphorylated tau protein, neuronal loss, brain atrophy, and chronic inflammation (Querfurth and Laferla, 2010). Astrocytes and microglial cells were extensively studied in the context of AD and are known to cluster around amyloid-β plaques When these cells become activated, they secrete a variety of pro-inflammatory mediators, potentially causing oxidative damage to neuronal and surrounding vascular tissue, and promote chronic inflammation (Akiyama et al, 2000; Querfurth and Laferla, 2010; Czirr and Wyss-Coray, 2012). This role was strongly supported by genome-wide association studies (GWAS) performed in the Myeloperoxidase Deficiency in Alzheimer’s Disease Mice last years identifying multiple loci within immune-related genes expressed by myeloid cells as susceptibility loci for AD (Hollingworth et al, 2011; Naj et al, 2011)
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