Distinct composition of different types of Abeta plaques in the pathogenesis of Alzheimer's disease and the role of neutrophil-derived myeloperoxidase.

Abstract

Alzheimer's disease (AD) is an age-related neurodegenerative disorder. Different types of Aβ plaques are likely to play distinct roles in the brains of patients with AD. In this study, through the combination of pathological techniques and analysis of the human brain database, we discovered that focal Aβ plaques (FAPs), rather than diffuse Aβ plaques (DAPs), are significantly correlated with AD-related neuropathological changes and cognitive impairment. By using laser capture microdissection in conjunction with microproteomics, the protein components of different Aβ plaques were characterized. Bioinformatic analysis indicated that FAP-enriched proteins are associated mainly with immune-related pathways, such as neutrophil extracellular trap formation. We further confirmed that myeloperoxidase (MPO) is significantly upregulated in the AD brain and colocalizes with FAPs but not with DAPs. Immunohistochemical staining demonstrated that neutrophils expressing MPO accumulated in the capillary lumen and brain parenchyma. The number of neutrophils significantly increases in the cortex and hippocampus of AD donors. Our study revealed a potential role for neutrophil-derived MPO in FAPs, providing insights into the pathogenesis mechanisms and potential therapeutic targets of AD.