Farnesylthiosalicylic Acid Through Inhibition of Galectin-3 Improves Neuroinflammation in Alzheimer Disease via Multiple Pathways

Aims: Many factors affect the neuroinflammatory response in patients with Alzheimer disease (AD). Galectin-3 (Gal-3) is closely related to microglial activation in the nervous system and can promote the aggregation of Cancer cells in tumors. This study aimed to investigate the mechanism by which farnesylthiosalicylic acid (FTS) affects neuroinflammation in Aβ_1-42 mice through Gal-3.

Methods: We used the Morris water maze, reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence to conduct our study.

Results: FTS reduced the levels of proinflammatory factors and microglial activation in Aβ_1-42 mice. FTS inhibited total and membrane expression levels of Gal-3 in Aβ_1-42 mice, and the anti-inflammatory effect of FTS was reversed by Gal-3-adeno-associated viral (AAV). FTS reduced the expression levels of toll-like receptors (TLRs), effects that were reversed by Gal-3-AAV. Moreover, FTS ameliorated Aβ oligomerization and accumulation in Aβ_1-42 mice, effects that were also reversed by Gal-3-AAV. FTS, through the inhibition of the Gal-3-c-Jun N-terminal kinase (JNK) pathway, reduced PS1 expression; in addition, inhibition of Gal-3 increased the Aβ-degrading Enzymes in Aβ_1-42 mice. FTS-induced improvements in cognition in Aβ_1-42 mice were reversed by Gal-3-AAV.

Conclusion: FTS may through inhibiting Gal-3 reduce the expression of TLR4 and CD14 and alleviate Aβ pathology, downregulating Aβ-stimulated TLR2, TLR4, and CD14 expression, and thus alleviate neuroinflammation in Aβ_1-42 mice.

Alzheimer disease; farnesylthiosalicylic acid; galectin‐3; neuroinflammation; toll‐like receptors; β‐amyloid.