Interleukin-17 (IL-17) triggers systemic inflammation, peripheral vascular dysfunction, and related prothrombotic state in a mouse model of Alzheimer's disease. (January 2023)

• Record Type: Journal Article
• Authors: Vellecco, Valentina; Saviano, Anella; Raucci, Federica; Casillo, Gian Marco; Mansour, Adel Abo; Panza, Elisabetta; Mitidieri, Emma; Femminella, Grazia Daniela; Ferrara, Nicola; Cirino, Giuseppe; Sorrentino, Raffaella; Iqbal, Asif Jilani; d'Emmanuele di Villa Bianca, Roberta; Bucci, Mariarosaria; Maione, Francesco
• Is Part Of: Pharmacological research. Volume 187(2023)
• Publication Date: 2023-01
• Subjects: Aβ amyloid‐β Ach acetylcholine -- AD Alzheimer's disease -- ADP Adenosine 5'-diphosphate disodium salt -- AUC area under the curve -- BLC B lymphocyte chemoattractant -- CCL-1 chemokine (C-C motif) ligand 1 -- CNS central nervous system -- COX- Cyclooxygenase- -- Ct cycle threshold -- CTRL Control -- CXCL9 chemokine (C-X-C motif) ligand 9 -- eNOS endothelial Nitric Oxide Synthase -- GCSF granulocyte-colony stimulating factor -- GM‐CSF granulocyte-macrophage colony-stimulating factor -- ICV intracerebroventricular -- IL interleukin- -- IL‐17Ab IL‐17A neutralizing antibody -- IL-17R IL-17 Receptor -- IN intranasal -- iNOS inducible Nitric Oxide Synthase -- IP-10 interferon gamma-induced protein 10 -- Iso isoprenaline -- KC keratinocyte chemoattractant -- MCP-1 monocyte-specific cytokine -- MCP-5 monocytes chemoattractant protein-5 -- MIPs macrophage inflammatory proteins -- NIA-AA U.S. National Institute on Aging-Alzheimer's Association -- NO Nitric Oxide -- PBS phosphate buffered saline -- PE phenylephrine -- PRP platelet-rich plasma -- PT prothrombin time -- PTT partial thromboplastin time -- qPCR quantitative PCR -- RANTES regulated on activation normal T cell expressed and secreted -- sICAM soluble intercellular adhesion molecule-1 -- TGF-β transforming growth factor-β -- Th T helper -- TIMP-1 tissue inhibitor of metallopeptidase inhibitor-1 -- TNF-α tumor necrosis factor-α -- Treg regulatory T cells; Alzheimer's disease -- IL-17 -- Immunological perturbance -- Systemic inflammation -- Vascular dysfunction; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2022.106595
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: Alzheimer's disease (AD) is one of the most prevalent forms of neurodegenerative disorders. Previously, we have shown that in vivo administration of an IL-17 neutralizing antibody (IL-17Ab) rescues amyloid‐β‐induced neuro-inflammation and memory impairment, demonstrating the pivotal role of IL-17 in AD-derived cognitive deficit. Recently, AD has been recognized as a more intriguing pathology affecting vascular networks and platelet function. However, not much is known about peripheral vascular inflammation and how pro-inflammatory circulating cells/mediators could affect peripheral vessels' function. This study aimed to evaluate whether IL‐17Ab treatment could also impact peripheral AD features, such as systemic inflammation, peripheral vascular dysfunction, and related pro-thrombotic state in a non-genetic mouse model of AD. Mice were injected intracerebroventricularly with Aβ1–42 peptide (3 μg/3 μl). To evaluate the systemic/peripheral protective profile of IL-17Ab, we used an intranasal administration of IL-17Ab (1 μg/10 μl) at 5, 12, and 19 days after Aβ1–42 injection. Circulating Th17/Treg cells and related cyto-chemokines, haematological parameters, vascular/endothelial reactivity, platelets and coagulation function in mice were evaluated. IL-17Ab treatment ameliorates the systemic/peripheral inflammation, immunological perturbance, vascular/endothelial impairment and pro-thrombotic state, suggesting a key role for this cytokine in fostering inflammatory processes that characterize the multifaced aspects of AD. Graphical Abstract: ga1 Highlights: Alzheimer's disease onset and progression are sustained by IL-17 with an impact on systemic/peripheral inflammation, endothelial impairment, and pro-aggregative state. Administration of a neutralizing-IL‐17A antibody rescues AD-related systemic/peripheral immunological and inflammatory-based disfunction of AD. The non-genetic mouse model of Aβ1–42 -induced Alzheimer's disease recapitulates the main features of pathology.