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Myeloperoxidase polymorphism is associated with gender specific risk for Alzheimer's disease
W F Reynolds1, J Rhees, D Maciejewski
1Sidney Kimmel Cancer Center, 10835 Altman Row, San Diego, California, 92121, USA. wreynolds@skcc.org
Abstract:
Myeloperoxidase (MPO) is a myeloid-specific enzyme that generates hypochlorous acid and other reactive oxygen species. MPO is present at high levels in circulating neutrophils and monocytes but is not detectable in microglia, brain-specific macrophages, in normal brain tissue. However, an earlier study indicated that MPO is present in macrophage-microglia at multiple sclerosis lesions, suggesting that reactivation of MPO gene expression may play a role in neurodegenerative diseases involving macrophage-microglia. In the present study, MPO is shown to colocalize with amyloid beta (Abeta) in senile plaques in cerebral cortex sections from Alzheimer's disease (AD) brain tissue. Microglia costaining for MPO and CD68 are closely associated with plaques, suggesting that plaque components induce MPO expression in microglia. In support of this interpretation, treatment of rodent microglia with aggregated Abeta(1-42) was shown to induce MPO mRNA expression. Also, the ApoE4 allele, the major AD risk factor associated with increased Abeta deposition, was shown to correlate with increased MPO deposition in plaques (P = 0.01, ANOVA). Finally, a genetic polymorphism links MPO expression to Alzheimer's risk, in that a higher expressing SpSp MPO genotype was associated with increased incidence of AD in females, and decreased incidence in males (P = 0.006). These findings suggest that the MPO polymorphism is a gender-specific risk factor for Alzheimer's disease.
Insights
Myeloperoxidase (MPO) is found in Alzheimer's disease plaques, suggesting it plays a role in neurodegeneration. A specific MPO gene variant is a gender-specific risk factor for developing Alzheimer's disease.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Myeloperoxidase (MPO) is an enzyme typically found in myeloid cells, not brain microglia.
- Previous research indicated MPO presence in microglia at multiple sclerosis lesions, suggesting a role in neuroinflammation.
- Alzheimer's disease (AD) is characterized by amyloid beta (Abeta) plaques and neuroinflammation.
Purpose of the Study:
- To investigate the presence and role of MPO in Alzheimer's disease pathology.
- To determine if Abeta aggregates induce MPO expression in microglia.
- To examine the association between MPO genetic variations, AD risk, and gender.
Main Methods:
- Immunohistochemical analysis of MPO and microglia markers (CD68) in AD brain tissue.
- In vitro treatment of rodent microglia with aggregated Abeta(1-42) to assess MPO mRNA expression.
- Statistical analysis of MPO deposition in plaques, ApoE4 allele, and MPO gene polymorphism incidence in AD patients stratified by gender.
Main Results:
- MPO colocalizes with amyloid beta (Abeta) in senile plaques in Alzheimer's disease brains.
- Microglia expressing MPO and CD68 are closely associated with Abeta plaques.
- Aggregated Abeta(1-42) induced MPO mRNA expression in microglia.
- The ApoE4 allele correlated with increased MPO deposition in plaques.
- A specific MPO genotype (SpSp) was associated with increased AD incidence in females and decreased incidence in males.
Conclusions:
- MPO is present in microglia within Alzheimer's disease plaques, suggesting its involvement in AD pathogenesis.
- Abeta deposition appears to induce MPO expression in microglia.
- MPO gene polymorphism represents a novel, gender-specific risk factor for Alzheimer's disease.