Caffeoylquinic Acid Mitigates Neuronal Loss and Cognitive Decline in 5XFAD Mice Without Reducing the Amyloid-β Plaque Burden

Background: Caffeoylquinic acid (CQA), which is abundant in coffee beans and Centella asiatica, reportedly improves cognitive function in Alzheimer’s disease (AD) model mice, but its effects on neuroinflammation, neuronal loss, and the amyloid-β (Aβ) plaque burden have remained unclear. Objective: To assess the effects of a 16-week treatment with CQA on recognition memory, working memory, Aβ levels, neuronal loss, neuroinflammation, and gene expression in the brains of 5XFAD mice, a commonly used mouse model of familial AD. Methods: 5XFAD mice at 7 weeks of age were fed a 0.8% CQA-containing diet for 4 months and then underwent novel object recognition (NOR) and Y-maze tests. The Aβ levels and plaque burden were analyzed by enzyme-linked immunosorbent assay and immunofluorescent staining, respectively. Immunostaining of markers of mature neurons, synapses, and glial cells was analyzed. AmpliSeq transcriptome analysis and quantitative reverse-transcription-polymerase chain reaction were performed to assess the effect of CQA on gene expression levels in the cerebral cortex of the 5XFAD mice. Results: CQA treatment for 4 months improved recognition memory and ameliorated the reduction of mature neurons and synaptic function-related gene mRNAs. The Aβ levels, plaque burden, and glial markers of neuroinflammation seemed unaffected. Conclusions: These findings suggest that CQA treatment mitigates neuronal loss and improves cognitive function without reducing Aβ levels or neuroinflammation. Thus, CQA is a potential therapeutic compound for AD, improving cognitive function via as-yet unknown mechanisms independent of reductions in Aβ or neuroinflammation.