Anti‐interleukin‐17A and anti‐interleukin‐23 antibodies may be effective against Alzheimer's disease: Role of neutrophils in the pathogenesis

Abstract Introduction Despite the remarkable progress achieved in the research on Alzheimer's disease (AD), its exact pathogenesis is not fully understood and effective therapies do not currently exist. In order to find effective therapy for AD, I ranged extensively over the literature and found an important paper by Tiffany and colleagues. Results and Conclusion Neuroinflammation has been proposed as a possible cause or driving force of AD. The discovery by Tiffany et al. that amyloid β (Aβ) is a formylpeptide receptor 2 agonist indicated that Aβ is a potent chemoattractant for phagocytic leukocytes. Therefore, in all likelihood Aβ attracts peripheral blood neutrophils, monocytes, as well as microglia cells in brain parenchyma, and activates them. However, the role of microglia cells and their precursor monocytes in AD pathogenesis remains elusive. Recently, neutrophils were found to be present in areas with Aβ deposits in AD brain and in transgenic AD model mice. Because brain is vulnerable to the effects of reactive oxygen species (ROS) and neutrophils secrete a large amount of ROS, neutrophils look like a driving force of AD. Therefore, a possibility arises that anti‐IL‐17A and anti‐IL‐23 antibodies are effective against AD, because these antibodies can be thought to interfere with neutrophil trafficking from the bone marrow to the blood circulation and thus inhibit neutrophil infiltration into AD brain. Clinical studies using anti‐IL‐17A and anti‐IL‐23 antibodies in patients with AD are required.


| EMERG EN CE OF AMYLOID -β ( A β)
Pathologically, AD is characterized by Aβ plaques, neurofibrillary tangles, in the advanced stage, neuronal loss in the neocortex and hippocampus. Aβ is a 36-43 amino acid peptide produced via sequential cleavage of amyloid precursor protein (APP), a transmembrane protein, by the enzymes β-and γ-secretase. Aβ monomers polymerize first into soluble oligomers and then into larger insoluble fibrils, which precipitate in the brain parenchyma as Aβ plaques (Haass, 2004). Neurofibrillary tangles are deposits in the neuronal body of tau, an abnormally phosphorylated microtubule-associated protein that interferes with cell function.

| NEUROINFL AMMATI ON IN AD
Although Aβ is directly toxic to cultured neurons in vitro (Mattson, 1997), neuroinflammation has also been proposed as a possible cause or driving force of AD (Wyss-Coray, 2006). Studies have reported elevated levels of inflammatory mediators in postmortem brains of patients with AD (Heppner, Ransohoff, & Becher, 2015). In the neuroinflammation hypothesis, activated microglia cells are considered key players in AD progression (Block, Zecca, & Hong, 2007;Hoeijmakers, Heinen, Dam, Lucassen, & Korosi, 2016), because microglia cells appear capable of producing superoxide (Shimohama et al., 2000) and various cytokines and chemokines, including IL-1, IL-6, TNFα, TGFβ1, TGFβ2, MIP1α, and MCP1 (Akiyama et al., 2000). However, another hypothesis states that microglia cells eliminate amyloid deposits using a cell-specific phagocytic mechanism (Simard, Soulet, Gowing, Julien, & Rivest, 2006). Therefore, whether microglial activation is detrimental or beneficial for patients with AD remains elusive (Daria et al., 2017;Wyss-Coray, 2006). By clinical experiments, using 11 C-(R)PK11195 and 11 C-PIB positron emission tomography and magnetic resonance imaging scans, Fan, Brooks, Okello, and Edison (2017) hypothesized that in the initial phase of AD, microglia cells try to repair neuronal damage, but in the later phase, they become ineffective and produce proinflammatory cytokines, leading to progressive neuronal damage. Tiffany et al. (2001) discovered that Aβ is a formyl peptide receptor 2 (FPR2) agonist. FPRs are largely responsible for the detection of invading bacteria, guiding phagocytes to the site of infection, and initiating a cascade of bactericidal activities (Bufe et al., 2015).

| A β IS A CHEMOAT TR AC TANT FOR PHAGOC Y TIC LEUKOC Y TE S
Briefly, formyl peptides are potent chemoattractants for phagocytic leukocytes (Dalpiaz et al., 2003;He, Troksa, Caltabiano, Pardo, & Ye, 2014;Le et al., 2002). Formyl peptides elicit robust, FPR-dependent calcium mobilization in human and mouse leukocytes and trigger a range of classical innate defense mechanisms, such as reactive oxygen species (ROS) production, metalloprotease release, and chemotaxis (Bufe et al., 2015). Currently, three functional FPRs have been reported in humans and mice: FPR1, FPR2 (FPR like1, FPRL1), and FPR3 (FPRL2) (Gallo et al., 2014;Liberles et al., 2009). In humans, FPR1 and FPR2 are expressed on both neutrophils and monocytes. The results obtained by Tiffany et al. indicate that Aβ is a potent chemoattractant and activator of phagocytic leukocytes. In addition, it was reported that in the experiment using microfluidic chemotaxis platform, Aβ (soluble form) continuously attracted human microglial cells for 90 hr (Cho et al., 2013).

| NEUTROPHIL S A S A C AUSATIVE FAC TOR FOR AD DE VELOPMENT
Neutrophils have not been a primary research subject of AD.
However, the presence of neutrophils in AD brain was shown by several investigators. Savage et al. (1994) detected cells expressing cathepsin G within AD brain parenchyma and cerebral blood vessels, often associated with Aβ deposits. Zenaro et al. (2015) identified myeloperoxidase + cells in areas with Aβ deposits.
Cationic antimicrobial protein 37 (CAP37), which is constitutively expressed in the azurophil granules of neutrophils, was shown in cerebral microcirculation (Grammas, 2000) and in temporal and parietal lobes as well as hippocampal neurons in AD patients (Brock et al., 2015). Studies using 2-photon microscopy revealed substantial neutrophil migration toward Aβ plaques in transgenic AD mice brain model (Baik et al., 2014;Zenaro et al., 2015). Once neutrophils migrate toward Aβ plaques, they are activated and secrete harmful mediators, including ROS. Because of its high demand for oxygen and the abundance of highly peroxidizable substrates , brain is vulnerable to the effects of ROS. According to Gandhi and Abramov (Gandhi & Abramov, 2012), brain of patients with AD shows evidence of ROS-mediated injury; there is an increase in malondialdehyde, 4-hydroxynonenal, and hydroxylated guanine levels in the brain and cerebrospinal fluid of AD patients. Protein carbonyl moieties are increased in the frontal and parietal cortices, and hippocampus in AD brain, with sparing of the cerebellum where no AD pathology occurs (Smith, Richey Harris, Sayre, Beckman, & Perry, 1997).
Another mechanism by which neutrophils damage AD brain is NETosis. Chemokines or ROS initiates a signaling cascade in neutrophils that leads to the disintegration of nuclear and cellular membranes and the formation of extracellular traps (ETs). Zenaro et al. (2015) and Pietronigro, Della Bianca, Zenaro, and Constantin (2017) observed intravascular and intraparenchymal NETosis in the mouse model of AD, potentially harming blood-brain barrier and neural cells. Taken together, these data suggest the involvement of neutrophils in AD progression.
Taken together, these data described above suggest that anti-IL-17A and anti-IL-23 antibodies, if administered to patients with AD, interfere with neutrophil infiltration into AD brain and inhibit AD progression.
A concern regarding administering anti-IL-17A and anti-IL-23 antibodies could be neutropenia. However, it seems that clinical trials on patients with psoriasis have not reported serious neutropenia.
Probably, in the broad sense of emergency granulopoiesis occurs to maintain neutrophil homeostasis, and this compensates the neutropenia induced by these antibodies. Emergency granulopoiesis is a G-CSF-independent process. Several models of neutropenia have shown IL-17A-independent feedback regulation of granulopoiesis, implicating redundancy in granulopoiesis-stimulating signals (Wirths et al., 2014).
Clinical studies using anti-IL-17A and anti-IL-23 antibodies in patients with AD are required.

ACK N OWLED G M ENT
I am the sole contributor of this manuscript.

CO N FLI C T O F I NTE R E S T
The author has no conflict of interests to declare. F I G U R E 1 IL-17A stimulates bone marrow (BM) stroma cells to secrete G-CSF, and G-CSF mediates granulopoiesis. Neutrophils in the BM are attached to stroma cell-derived factor-1α (SDF-1α), which is present in BM stroma or on the surfaces of osteoblasts, reticular cells, and endothelial cells. The attachment is mediated by CXCR4 on neutrophil surfaces. G-CSF downregulates CXCR4 expression on neutrophils and reduces SDF-1α level in the BM, disrupting the attachment. Neutrophils released from SDF-1α migrate into peripheral circulation to keep neutrophil homeostasis. Anti-IL-17A antibody interferes with IL-17A-mediated granulopoiesis and neutrophil migration from the BM and presumably interrupt neutrophil infiltration into AD brain

DATA AVA I L A B I L I T Y S TAT E M E N T
All data generated or analyzed during this study are included in this published article.