Compound (E)-2-(3,4-dihydroxystyryl)-3-hydroxy-4H-pyran-4-one downregulation of Galectin-3 ameliorates Aß pathogenesis-induced neuroinflammation in 5 × FAD mice.

Alzheimer's disease (AD) is characterized by ß-amyloid (Aß) aggregation and neuroinflammation, leading to a progressive synaptic loss and cognitive decline. Recent evidence highlights Galectin-3 (Gal-3) as a crucial factor in Aß pathogenesis, yet effective strategies to simultaneously target Gal-3 and Aß are currently insufficient. This study assesses the therapeutic efficacy of D30, an innovative anti-AD compound manifested promising effects on reducing Aß deposition and alleviating neuronal damage in scopolamine-induced AD models. In our study, we administered neurotoxic oligomeric Aß (oAß) to mice and observed increased Gal-3 deposition and microglial activation in the hippocampus, leading to significant cognitive impairments. Similarly, in the 5 × FAD mouse model, known for Aß overproduction, there was a progressive rise in Gal-3 levels and glial cell activation. We then investigated the effects of D30 on 5 × FAD mice, focusing on its modulation of Gal-3 and Aß and impact on neuroinflammatory responses. D30 effectively reduced Aß monomer production by inhibiting the expression of Amyloid Precursor Protein (APP) and presenilin 1 (PS1), as well as decreasing Aß oligomer aggregation. Treatment with D30 not only improved cognitive functions but also reversed dendritic spine loss and increased PSD95 expression in 5 × FAD mice. Notably, D30 significantly lowered Gal-3 levels in both plasma and hippocampal tissues. Mechanistic studies revealed that D30 binds to Gal-3 and disrupts the interaction between Gal-3 and the triggering receptor expressed on myeloid cells 2 (TREM2), as confirmed by fluorescence resonance energy transfer (FRET) and microscale thermophoresis (MST). Our findings underscore the interaction between Gal-3 and Aß in AD and its role in systemic inflammation using the 5 × FAD mouse model. Being able to target and regulate Gal-3 together with Aß is crucial for preventing neuroinflammation and protecting neurons, D30 emerged as a novel compound with promising potential for AD treatment. AIMS: Alzheimer's disease (AD) is characterized by ß-amyloid (Aß) aggregation and neuroinflammation, leading to progressive synaptic loss and cognitive decline. Recent evidence suggests that Galectin-3 (Gal-3) plays a critical role in Aß pathogenesis. However, strategies to simultaneously target Gal-3 and Aß are currently insufficient. This study evaluates the therapeutic efficacy of D30, in reducing Gal-3 and Aß pathogenesis. MATERIALS AND METHODS: We applied exogenous oligomeric Aß and used 5 × FAD mice to assess the impact of Aß on Gal-3 deposition, microglial activation, and cognitive function. Thy1-EGFP mice were employed to observe dendritic spines. Comprehensive evaluations of D30's effects included behavioral studies, transcriptomic analysis, Western blotting, and immunofluorescent staining. The interaction between D30 and Gal-3 was examined using fluorescence resonance energy transfer (FRET) and microscale thermophoresis (MST). KEY FINDINGS: D30 effectively reduced Aß monomer production by inhibiting Amyloid Precursor Protein (APP) and presenilin 1 (PS1) expression, and decreased Aß aggregation. Treatment with D30 improved cognitive functions, reversed dendritic spine loss, and increased PSD95 expression in 5 × FAD mice. Additionally, D30 significantly lowered Gal-3 levels in both plasma and hippocampal tissues. D30 binds to Gal-3 and disrupts the interaction between Gal-3 and TREM2, as confirmed by FRET and MST. SIGNIFICANCE: Our findings underscore the interaction between Gal-3 and Aß in AD and its role in systemic inflammation using the 5 × FAD mouse model. Being able to target and regulate Gal-3 together with Aß is crucial for preventing neuroinflammation and protecting synapses, D30 emerged as a novel compound with promising potential for AD treatment.