This present study examined the effect of Tamibarotene (AM80) in APP/PS1 mice, a well-established AD mouse model. AM80 was intraperitoneal administered to 3-month-old APP/PS1 mice at a dose of 5 mg/kg/day for 16 weeks. The results clearly showed that AM80 could reduce amyloid-β peptides through impact on APP processing and reduce microglia and astrocyte activation in APP/PS1 mice. The most notable finding in the present study was that inhibitory effect on BACE1 mediated by NF-κB pathway underlies the anti-inflammatory action of AM80. Moreover, AM80 could significantly decrease synaptic loss and enhance the expressions of Synapsin and Drebrin. Therefore, AM80 treatment may have the preclinical prevention of AD with new therapeutic strategies.

Matrine, a quinoline alkaloid, possesses lipid-regulating effects, but the underlying mechanisms are rarely characterized in vivo. With a fat-accumulating Caenorhabditis elegans model, we show that matrine reduces the fat content and the DHS-3::GFP-labeled lipid droplets in high-glucose-diet N2 and transgenic LIU1 nematodes, respectively. Based on RNA-seq, this study demonstrates that a loss of AAK-2 function suppresses the fat-lowering effects of matrine, and the hyperactivated AAK-2 strain has a relatively lower fat content than N2. The involvement of NHR-49 in matrine’s fat-lowering effects further suggests that matrine impacts fat breakdown and storage via the AAK-2/NHR-49-governed pathway. Using the transgenic SJ4143 (ges-1::GFP(mit)) and VS10 (vha-6p::mRFP-PTS1), we show that matrine activates the AAK-2/NHR-49 pathway, coupling the alteration of mitochondrial and peroxisomal functions. Studies of aak-2 and nhr-49 mutants reveal that AAK-2 and NHR-49 modulate lipid metabolic homeostasis; meanwhile, matrine increases physical fitness and lifespan through activating the AAK-2/NHR-49 pathway in high-glucose-diet nematodes. Surprisingly, we found that β-amyloid (Aβ) induces lipid metabolic disorder in an Alzheimer’s disease (AD) C. elegans model, but matrine not only reduces Aβ aggregation but also alleviates Aβ-mediated lipid metabolic disorder. Our data suggest that matrine has promise as a fat-lowering agent, and also offer new insights into its therapeutic potential for AD.