Carprofen alleviates Alzheimer-like phenotypes of 5XFAD transgenic mice by targeting the pathological hallmarks induced by amyloid-β aggregation

Alzheimer's disease (AD) is characterized by misfolding, oligomerization, and accumulation of amyloid-& beta; (A & beta;) peptides in the brain. A & beta; monomers transform into A & beta; oligomers, which are toxic species, inducing tau hyperphosphorylation and the downstream effects on microglia and astrocytes, triggering synaptic and cognitive dysfunctions. The oligomers then deposit into A & beta; plaques, primarily composed of & beta;-stranded fibrils, required for definitive AD diagnosis. As amyloid burden plays the pivotal role in AD pathogenesis, many efforts are devoted in preventing amyloidosis as a therapeutic approach to impede the disease progression. Here, we discovered carprofen, a non-steroidal anti-inflammatory drug, accelerates A & beta; aggregating into fibrils and increases A & beta; plaques when intraperitoneally injected to 5XFAD transgenic mouse model. However, the drug seems to alleviate the key Alzheimer-like phenotypes induced by A & beta; aggregation as we found attenuated neuroinflammation, improved post-synaptic density expression, associated with synaptic plasticity, and decreased phosphorylated tau levels. Carprofen also rescued impaired working memory as we discovered improved spontaneous alternation performance through Y-maze test assessed with A & beta;(1-42)-infused mouse model. Collectively, while carprofen accelerates the conversion of A & beta; monomers into fibrils in vitro, the drug ameliorates the major pathological hallmarks of AD in vivo.