Neutrophil Extracellular Traps: A Perspective of Neuroinflammation and Complement Activation in Alzheimer's Disease

Abstract

Complement system (CS) components are associated with Alzheimer's disease (AD), the commonest cause of dementia in the world. Neutrophils can be attracted to amyloid-β plaques by several pro-inflammatory factors, including the complement anaphylatoxin C5a. They may release neutrophil extracellular traps (NETs), which are chromatin nets associated with myeloperoxidase, elastase, and other enzymes. Some CS molecules, such as C5a, C1q, and CR1, are associated with increased neutrophil recruitment and NETs release. However, the relationship between CS molecules and NETs in AD is poorly understood. In this work, we detected higher NET concentrations in plasma and serum of Brazilian AD patients, than in elderly controls (medians = 2.78 [2.07-6.19] vs. 2.23 [0.33-4.14] ng/mL, p = 0.0005). We discussed these results within the context of our former findings on complement and AD and the context of the literature on complement and NET release, suggesting both as possible therapeutic targets to prevent the progress of the disease.

Keywords: Alzheimer's Disease; C1q; C5a; CR1; complement system; inflammation; neutrophil extracellular traps.

FIGURE 1

Possible involvement of the complement system (CS) in the recruitment of neutrophils and the formation of NETs in Alzheimer's disease. When the blood-brain barrier (BBB) is intact, most complement molecules do not pass through it but can be produced constitutively by brain cells. In AD, the BBB is compromised, facilitating the passage of complement elements, among other pro-inflammatory elements (Alexander, 2018). Aβ plaques are recognized as DAMPs by CS components and other innate immunity receptors, leading to the activation of BBB endothelial cells. They up-regulate ICAM-1 adhesion molecules, allowing neutrophils to adhere and interact with LFA-1, invading the cerebral parenchyma (Pietronigro et al., 2017). There the neutrophils worsen neuroinflammation, performing NET extrusion. In this context, the CS may be involved trough: (1) C1q binding to the Aβ plates, activating the classical complement pathway; (2a) CR1 (CR1*A) molecules present in the neutrophil membrane, that recognize the Aβ plates opsonized with C3b fragments, preferentially leading to NET extrusion; (2b) soluble CR1 formed by non-functional isoforms (CR1*B) that do not inhibit the CS (3) Potent anaphylatoxins such as C5a, which recruit neutrophils from the periphery to the Aβ plaque, being recognized by C5aR1 neutrophil receptors, promoting the release of NETs. Although other elements of the inflammatory reaction do occur, in this figure, we focus on elements of the CS discussed throughout this study. The complement cascades’ reactions were not represented due to space and number of elements participating in the pathways. The role of cytokines and endothelial adhesion molecules in neutrophil recruitment for Aβ plaques was extensively reviewed by Pietronigro et al. (2017) ICAM-1- Intercellular adhesion molecule 1; LFA-1- Lymphocyte function-associated antigen 1; NET- extracellular neutrophil traps; CS- complement system; C1q- complement component 1q; CR1- complement receptor 1; C3b- complement component 3b; C5a- complement component 5a; C5aR1- complement component 5a receptor. This figure was created with BioRender.com.

FIGURE 2

NETs concentration between AD patients and controls. Differences in NETs concentration between: (A)—AD patients and elderly controls. (B)—AD patients and elderly controls in High (H) and Low (L) groups. *p ≤ 0.01; **p ≤ 0.05.