TSPO Modulates Oligomeric Amyloid--Induced Monocyte Chemotaxis: Relevance for Neuroinflammation in Alzheimer's Disease
Journal of Alzheimer's disease : JAD(2023)
摘要
Background: Neuroinflammation is one of the cardinal mechanisms of Alzheimer's disease (AD). with amyloid-beta (A beta) 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 A beta 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 A beta(1-42) 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 mu-slide chambers and Boyden assays, using 125 pM oligomeric A beta(1-42) as chemoattractant. TSPO agonists and antagonists were tested (Ro5-4864, Emapunil, PK11195). Results: Oligomeric A beta directly promoted chemotaxis in all our models. Interestingly, AD monocytes displayed a stronger response (about twofold) with respect to controls. A beta-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 A beta(1-42) 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.
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关键词
Alzheimer's disease, amyloid-beta, chemotaxis, monocytes, neuroinflammation, PK11195, TSPO
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