Phytochemical regulation of CaMKII in Alzheimer’s disease: A review of molecular mechanisms and therapeutic potential

Alzheimer’s disease (AD) is a common neurodegenerative disorder that leads to cognitive decline. CaMKII is a calcium-regulated kinase that is crucial for synaptic plasticity and memory. Phytochemicals with diverse origins, safety, and biological activity have attracted considerable attention in AD research. This systematic analysis of phytochemicals targeting CaMKII reveals their neuroprotective mechanisms against AD pathogenesis, highlighting CaMKII as a promising therapeutic target that warrants further preclinical investigation and drug development. We conducted a comprehensive review of the literature of phytochemicals that target CaMKII as a protective mechanism against AD. The search was conducted across multiple databases, including PubMed, Web of Science, China National Knowledge Internet, and Google Scholar, and covered the period from January 2000 to October 2024. A total of 301 articles were retrieved, of which 22 articles were included. The results showed that flavonoid, glycoside, terpene, and polyphenol analogs positively regulated CaMKII expression, whereas alkaloid analogs negatively regulated CaMKII expression. Different components of traditional Chinese medicine played different roles in CaMKII expression. Flavonoid compounds upregulated the expression of SYN, PSD-95, MAP2, and GluR1 to exert neuroprotective effects. Alkaloid and glycoside analogs inhibited Aβ deposition and tau hyperphosphorylation. Terpene analogs upregulated the SYN, PSD-95, NMDAR, BDNF, and PI3K/Akt signaling pathways to exert neuroprotection. Polyphenol analogs upregulated PSD-95, Munc18–1, SNAP25, SYN, and BDNF to exert neuroprotective effects. Emerging evidence demonstrates that select phytochemicals and traditional Chinese medicine compounds exert neuroprotective effects in AD by modulating CaMKII activity, thereby reducing Aβ accumulation, attenuating tau hyperphosphorylation, and enhancing synaptic plasticity, suggesting promising therapeutic potential.