TSPO Modulates Oligomeric Amyloid-β-Induced Monocyte Chemotaxis: Relevance for Neuroinflammation in Alzheimer’s Disease

Article type: Research Article

Authors: Conti, Elisa^{a; b} | Grana, Denise^{a; b} | Angiulli, Federica^{a; b} | Karantzoulis, Aristotelis^{b; c} | Villa, Chiara^{a; b} | Combi, Romina^{a; b} | Appollonio, Ildebrando^{a; b; c} | Ferrarese, Carlo^{a; b; c} | ImmunAD-Brianza Network^{a; b; c; 1} | Tremolizzo, Lucio^{a; b; c; *}

Affiliations: [a] School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy | [b] Milan Center for Neuroscience (NeuroMi), Italy | [c] Memory Clinic, Neurology Unit, IRCCS “San Gerardo dei Tintori”, Monza, Italy

Correspondence: [*] Correspondence to: Lucio Tremolizzo, MD, PhD, University of Milano-Bicocca – Italy, Room 2043, Building U8 - via Cadore 48, Monza 20900 MB, Italy. Tel.: +39 02 6448 8128; E-mail: [email protected].

Note: [1] ImmunAD-Brianza Network: Angelo Aliprandi (Lecco), Simona Andreoni (Monza), Vittoria Aprea (Monza), Chiara Bazzini (Monza), Massimiliano Cadamuro (Monza), Mario Bossi (Monza), Fulvio Da Re (Monza), Giulia Negro (Monza), Federico Emanuele Pozzi (Monza), Giulia Remoli (Monza), Virginia Rodriguez Menendez (Monza), Gessica Sala (Monza), Andrea Salmaggi (Lecco), Chiara Paola Zoia (Monza).

Abstract: Background:Neuroinflammation is one of the cardinal mechanisms of Alzheimer’s disease (AD). with amyloid-β (Aβ) playing a critical role by activating microglia to produce soluble inflammatory mediators, including several chemokines. Peripheral monocytes are, therefore, attracted into the central nervous system (CNS), where they change into blood-born microglia and participate in the attempt of removing toxic Aβ species. The translocator protein-18 kDa (TSPO) is a transmembrane protein overexpressed in response to neuroinflammation and known to regulate human monocyte chemotaxis. Objective:We aimed to evaluate the role of the oligomeric Aβ1-42 isoform at inducing peripheral monocyte chemotaxis, and the possible involvement of TSPO in this process. Methods:In vitro cell lines, and ex vivo monocytes from consecutive AD patients (n = 60), and comparable cognitively intact controls (n = 30) were used. Chemotaxis analyses were carried out through both μ-slide chambers and Boyden assays, using 125 pM oligomeric Aβ1-42 as chemoattractant. TSPO agonists and antagonists were tested (Ro5-4864, Emapunil, PK11195). Results:Oligomeric Aβ directly promoted chemotaxis in all our models. Interestingly, AD monocytes displayed a stronger response (about twofold) with respect to controls. Aβ-induced chemotaxis was prevented by the TSPO antagonist PK11195; the expression of the TSPO and of the C-C chemokine receptor type 2 (CCR2) was unchanged by drug exposure. Conclusion:Oligomeric Aβ1-42 is able to recruit peripheral monocytes, and we provide initial evidence sustaining a role for TSPO in modulating this process. This data may be of value for future therapeutic interventions aimed at modulating monocytes motility toward the CNS.

Keywords: Alzheimer’s disease, amyloid-β, chemotaxis, monocytes, neuroinflammation, PK11195, TSPO

DOI: 10.3233/JAD-230239

Journal: Journal of Alzheimer's Disease, vol. 95, no. 2, pp. 549-559, 2023